This invention is in the field of treating cardiovascular disease, and specifically relates to compounds, compositions and methods for treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted polycyclic aryl and heteroaryl tertiary-heteroalkylamine compounds that inhibit cholesteryl ester transfer protein (CEFP), also known as plasma lipid transfer protein-I.
Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis, 121, 1-12 (1996)). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.
Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDL/LDL ratios. Inhibition of CETP by the subject compounds is shown to effectively modify plasma HDLJLDL ratios, and to check the progress and/or formation of these diseases.
CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res., 34, 1255-74 (1993)). The movement of cholesteryl ester from HDL to LDL by CETP has the effect of lowering RDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy, Medicinal Res. Revs., 13, 139-59 (1993); Sitori, Pharmac. Ther., 67,443-47 (1995)). This exact phenomenon was first demonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (Biochim. Biophys. Acta 795, 743-480 (1984)), Morton et al. (J. Lipid Res. 35, 836-847 (1994)) and Tollefson et al. (Am. J. Physiol., 255, (Endocrinol. Metab. 18, E894-E902 (1988))) describe proteins from human plasma that inhibit CETP. U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity. Cho et al. (Biochim. Biophys. Acta 1391, 133-144 (1998)) describe a peptide from hog plasma that inhibits human CETP. Bonin et al. (J. Peptide Res., 51, 216-225 (1998)) disclose a decapeptide inhibitor of CETP. A depsipeptide fungal metabolite is disclosed as a CEFP inhibitor by Hedge et al. in Bioorg. Med. Chem. Lett., 8, 1277-80 (1998).
There have been several reports of non-peptidic compounds that act as CETP inhibitors. Barrett et al. (J. Am. Chem. Soc., 188, 7863-63 (1996)) and Kuo et al. (J. Am. Chem. Soc., 117, 10629-34 (1995)) describe cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med. Chem. Lett, 6, 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. Lett., 5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds as CETP inhibitors. Japanese Patent Application No. 10287662-A describes polycyclic, non-amine containing, polyhydroxylic natural compounds possessing CETP inhibition properties. Lee et al. (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25, 216-220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Connolly et al. (Biochem. Biophys. Res. Comm. 223, 42-47 (1996)) describe other cysteine modification reagents as CETP inhibitors. Xia et al. describe 1,3,5-triazines as CETP inhibitors (Bioorg. Med. Chem. Lett., 6, 919-22 (1996)). Bisgaier et al. (Lipids, 29, 811-8 (1994)) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor. Oomura et al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETP inhibitors in Japanese Patent Application No. 10287662. In WO Patent Application No. 09914204, Sikorski describes 1,2,4-triazolylthiols useful as chlolesteryl ester transfer protein inhibitors.
Some substituted heteroalkylamine compounds are known. In European Patent Application No. 796846, Schmidt et al. describe 2-aryl-substituted pyridines as cholesteryl ester transfer protein inhibitors useful as cardiovascular agents. One substitutent at C3 of the pyridine ring can be an hydroxyalkyl group. In European Patent Application No. 801060, Dow and Wright describe heterocyclic derivatives substituted with an aldehyde addition product of an alkylamine to afford 1-hydroxy-1-amines. These are reported to be xcex23-adrenergic receptor agonists useful for treating diabetes and other disorders. In Great Britain Patent Application No. 2305665, Fisher et al. disclose 3-agonist secondary amino alcohol substituted pyridine derivatives useful for treating several disorders including cholesterol levels and artherosclerotic diseases. In European Patent Application No. 818448, Schmidt et al. describe tetrahydroquinoline derivatives as chlolesteryl ester transfer protein inhibitors. European Patent Application No. 818197, Schmek et al. describe pyridines with fused heterocycles as cholesteryl ester transfer protein inhibitors. Brandes et al. in German Patent Application No. 19627430 describe bicyclic condensed pyridine derivatives as cholesteryl ester transfer protein inhibitors. In WO Patent Application No. 09839299, Muller-Gliemann et al. describe quinoline derivatives as cholesteryl ester transfer protein inhibitors. U.S. Pat. No. 2,700,686, issued to Dickey and Towne, describes N-(2-haloalkyl-2-hydroxyethyl)amines in which the amine is further substituted with either 1 to 2 aliphatic groups or one aromatic group and one aliphatic group. U.S. Pat. No. 2,700,686 further describes a process to prepare the N-(2-haloalkyl-2-hydroxyethyl)amines by reacting halogenated-1,2-epoxyalkanes with the corresponding aliphatic amines and N-alkylanilines and their use as dye intermediates.
The present invention provides compounds that can be used to inhibit cholesteryl ester transfer protein (CE7P) activity and that have the general structure: 
In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier.
In another aspect, this invention relates to methods of using these inhibitors as therapeutic agents in humans to inhibit cholesteryl ester transfer protein (CETP) activity, thereby decreasing the concentrations of low density lipoprotein (LDL) and raising the level of high density lipoprotein (HDL), resulting in a therapeutically beneficial plasma lipid profile. The compounds and methods of this invention can also be used to treat dyslipidemia (hypoalphalipoproteinemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinemia), peripheral vascular disease, hypercholesterolaemia, atherosclerosis, coronary artery disease and other CETP-mediated disorders. The compounds can also be used in prophylactic treatment of subjects who are at risk of developing such disorders. The compounds can be used to lower the risk of atherosclerosis. The compounds of this invention would be also useful in prevention of cerebral vascular accident (CVA) or stroke. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals such as primates, rabbits, pigs, horses, and the like.
The present invention relates to a class of compounds comprising substituted polycyclic aryl and heteroaryl tertiary-heteroalkylamines which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula V-H (also referred to herein as generic substituted polycyclic aryl and heteroaryl tenay omegaheteroalkylamines): 
or a pharmaceutically acceptable salt thereof, wherein;
m is an integer selected from 0 through 5;
n is an integer selected from 0 through 5;
m plus n is an integer selected from 0 through 6;
R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
X is selected from the group consisting of O, H, F, S, S(O), NH, N(OH), N(alkyl), and N(alkoxy);
R16 is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of an aromatic substituent selected from the group consisting of R4, R8, R9, R13, R14, and R15 to form a heterocyclyl ring having from 5 through 10 contiguous members with the provisos that said spacer moiety is other than a covalent single bond when R2 is alkyl and there is no R16 wherein X is H or F;
D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D1, D2, J1, J2 and K1 can be a covalent bond, no more than one of D1, D2, J1, J2 and K1 can be O, no more than one of D1, D2, J1, J2 and K1 can be S, one of D1, D2, J1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 can be N;
D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D3, D4, J3, J4 and K2 can be a covalent bond, no more than one of D3, D4, J3, J4 and K2 can be O, no more than one of D3, D4, J3, J4 and K2 can be S, one of D3, D4, J3, J4 and K2 must be a covalent bond when two of D3, D4, J3, J4 and K2 are O and S, and no more than four of D3, D4, J3, J4 and K2 can be N;
R2 is independently selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamnino, dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;
R2 and R3 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
R2 and R14 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear spacer moiety having from 1 through 5 contiguous atoms to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that said spacer group is other than xe2x80x94Nxe2x95x90;
R2 and R15 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear spacer moiety having from 1 through 5 contiguous atoms to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that said spacer group is other than xe2x80x94Nxe2x95x90;
R2 and R19 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a linear moiety having from 1 through 5 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkylenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
R2 and R4, R2 and R8, R2 and R9, and R2 and R13 can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear spacer moiety wherein said linear spacer moiety is selected to form a heterocyclyl ring having from 5 through 10 contiguous members;
R3 is selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamiino, dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl, heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;
R3 and R14 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear moiety having from 1 through 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;
R3 and R15 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent bond and a linear moiety having from 1 through 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;
R3 and R19 can be taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a linear moiety having a chain length of 1 to 5 atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkylenyl having from 5 through 8 contiguous members, and a saheterocyclyl having from 4 through 8 contiguous members;
R3 and R4, R3 and R8, R3 and R9, and R3 and R13 can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear spacer moiety wherein said linear spacer moiety is selected to form a heterocyclyl ring having from 5 through 10 contiguous members;
Y is selected from a group consisting of a covalent single bond, (C(R14)2)q wherein q is an integer selected from 1 through 4 and (CH(R14))gxe2x80x94Wxe2x80x94(CH(R14))p wherein g and p are integers independently selected from 0 through 2;
R14 is independently selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R9 and R13 to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R4 and R8 to form a heterocyclyl having from 5 through 8 contiguous members with the proviso that, when Y is a covalent bond, an R14 substituent is not attached to Y;
R14 and R15 can be taken together to form a spacer selected from a moiety having a chain length of 2 to 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;
R14 and R19 can be taken together to form a spacer selected from a moiety having a chain length of 2 to 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;
R14 and R14, when bonded to the different atoms, can be taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
R14 and R14, when bonded to the same atom can be taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
W is selected from the group consisting of O, C(O), C(S), C(O)N(R14), C(S)N(R14), (R14)NC(O), (R14)NC(S), S, S(O), S(O)2, S(O)2N(R14), (R14)NS(O)2, and N(R14) with the proviso that R14 is selected from other than halo and cyano;
Z is independently selected from a group consisting of a covalent single bond, (C(R15)2)q wherein q is an integer selected from 1 through 4, (CH(R15))jxe2x80x94Wxe2x80x94(CH(R15))k wherein j and k are integers independently selected from 0 through 2 with the proviso that, when Z is a covalent single bond, an R15 substituent is not attached to Z;
R15 is independently selected, when Z is (C(R15)2)q wherein q is an integer selected from 1 through 4, from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R4 and R8 to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a heterocyclyl ring having from 5 through 8 contiguous members, and a spacer selected from a moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R9 and R13 to form a heterocyclyl having from 5 through 8 contiguous members;
R15 and R19 can be taken together to form a spacer selected from the group consisting of a covalent single bond and a linear moiety having a chain length of 2 to 5 atoms to form a heterocyclyl ring having from 5 through 8 contiguous members;
R15 and R15, when bonded to the different atoms, can be taken together to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a spacer selected from a group consisting of a moiety having a chain length of 2 to 5 atoms connected to form a ring selected from the group of a saturated cycloalkyl having from 5 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
R15 and R15, when bonded to the same atom can be taken together to form a group selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a spacer selected from the group consisting of a moiety having a chain length of 3 to 7 atoms connected to form a ring selected from the group consisting of a cycloalkyl having from 4 through 8 contiguous members, a cycloalkenyl having from 4 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
R15 is independently selected, when Z is (CH(R15))jxe2x80x94Wxe2x80x94(CH(R15))k wherein j and k are integers independently selected from 0 through 2, from the group consisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl, heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected from a linear moiety having a chain length of 3 to 6 atoms connected to the point of bonding selected from the group consisting of R4 and R8 to form a ring selected from the group consisting of a cycloalkenyl ring having from through 8 contiguous members and a heterocyclyl ring having from through 8 contiguous members, and a spacer selected from a linear moiety having a chain length of 2 to 5 atoms connected to the point of bonding selected from the group consisting of R9 and R13 to form a heterocyclyl ring having from 5 through 8 contiguous members;
R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylaamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylaamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the proviso that there are one to five non-hydrido ring substituents R4, R5, R6, R7, and R8 present, that there are one to five non-hydrido ring substituents R9, R10, R11, R12, and R13 present, and R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11 R11 and R12, and R12 and R13 can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R12, and R12 and R13 can be used at the same time;
R4 and R9, R4 and R13, R8 and R9, and R8 and R13 can be independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a ring selected from the group consisting of a partially saturated heterocyclyl ring having from 5 through 8 contiguous members and a heteroaryl ring having from 5 through 6 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R4 and R9, R4 and R13, R8 and R9, and R8 and R13 can be used at the same time;
R5 and R10, R5 and R12, R7 and R10, and R7 and R12 can be independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear moiety wherein said linear moiety forms a C8 to C13 heterocyclyl ring having from 8 through 13 contiguous members with the proviso that no more than one of the group consisting of spacer pairs R5 and R10, R5 and R12, R7 and R10, and R7 and R12 can be used at the same time;
R19 is selected from the group consisting of hydrido, hydroxyalkyl, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkanoyl, heteroarylthio, aralkylthio, aroyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, and a spacer group selected from the group consisting of a covalent single bond and a linear moiety having a chain length of 2 to 5 atoms connected to a point of bonding selected from the group consisting of R4, R8, R9, and R13 to form a heterocyclyl ring having from 5 through 8 contiguous members.
In another embodiment, the compounds correspond to Formula V-H wherein m is an integer selected from 0 through 5; n is an integer selected from 0 through 5; the sum of m plus n is an integer selected from 0 through 6; D1, D2, D3, D4, J1, J2, J3, J4, K1, and K2 are each a carbon atom; and a terminal carbon atom of the CH(R3) moiety is directly connected by a covalent single bond to the nitrogen when m=0. Compounds of Formula V-H wherein m is an integer selected from 0 through 5, n is an integer selected from 0 through 5, the sum of m plus n is an integer selected from 0 through 6, and D1, D2, D3, D4, J1, J2, J3, J4, K1, and K2 are each a carbon atom, have the CH(R3) moiety directly connected by a covalent single bond to the nitrogen when m=0 and correspond to Formula V (also referred to herein as generic phenyl tertiary omegaheteroalkylamines): 
or a pharmaceutically acceptable salt thereof, wherein;
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R19, X, Y, and Z are as defined for the compounds of Formula V-H;
D1, D2, D3, D4, J1, J2, J3, J4, K1, and K2 are each carbon;
R16 and R4, R16 and R8, R16 and R9, R16 and R13, R2 and R3, R9 and R14, R13 and R14, R4 and R14, R8 and R14, R14 and R14, R4 and R15, R8 and R15, R9 and R15, R13 and R15, R15 and R15, R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R12, R12 and R13, R4 and R9, R4 and R13, R8 and R9, R8 and R13, R16 and R14, R16 and R15, R2 and R14, R2 and R15, R2 and R19, R2 and R4, R2 and R8, R2 and R9, R2 and R13, R3 and R14, R3 and R15, R3 and R19, R3 and R4, R3 and R8, R3 and R9, R3 and R13, R14 and R19, R14 and R15, R15 and R19, R5 and R10, R5 and R12, R7 and R10, and R7 and R12 spacer pairs are as defined for the compounds of Formula V-H.
In another embodiment, the compounds correspond to Formula V-H wherein m is an integer selected from 0 through 5; n is an integer selected from 0 through 5; the sum of m plus n is an integer selected from 0 through 6; and a terminal carbon atom of the CH(R3) moiety is directly connected by a covalent single bond to the nitrogen when m=0. Compounds of Formula V-H wherein wherein m is the integer zero, and n is an integer selected from 0 through 5, have the CH(R3) moiety directly connected by a covalent single bond to the nitrogen when m=0 and correspond to Formula VII-H (also referred to herein as generic substituted polycyclic heteroaryl tertiary 2-heteroalkylamines): 
or a pharmaceutically acceptable salt thereof, wherein;
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, D1, D2, D3, D4, J1, J2, J3, J4, K1, K2, X, Y, and Z are as defined for the compounds of Formula V-H;
R16 and R4, R16 and R8, R16 and R9, R16 and R13, R2 and R3, R9 and R14, R13 and R14, R4 and R14, R8 and R14, R14 and R14, R4 and R15, R8 and R15, R9 and R15, R13 and R15, R15 and R15, R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R12, R12 and R13, R4 and R9, R4 and R13, R8 and R9, and R8 and R13 spacer pairs are as defined for the compounds of Formula V-H;
R19 and spacer pairs R16 and R14, R16 and R15, R2 and R14, R2 and R15, and R2 and R19, R2 and R4, R2 and R8, R2 and R9, R2 and R13, R3 and R14, R3 and R15, R3 and R19, R3 and R4, R3 and R8, R3 and R9, R3 and R13, R14 and R19, R14 and R15, R15 and R19, R5 and R10, R5 and R12, R7 and R10, and R7 and R12 are not present.
In another embodiment of compounds of Formula VII-H,
D1, D2, J1, J2 and K1 are each carbon with the proviso that at least one of D3, D4, J3, J4 and K2 is selected from the group consisting of O, S, and N, wherein D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of D3, D4, J3, J4 and K2 can be a covalent bond, no more than one of D3, D4, J3, J4 and K2 can be O, no more than one of D3, D4, J3, J4 and K2 can be S, one of D3, D4, J3, J4 and K2 must be a covalent bond when two of D3, D4, J3, J4 and K2 are O and S, and no more than four of D3, D4, J3, J4 and K2 can be N;
D1, D2, J1, J2 and K1 can be selected from the group consisting of C, O, S, N and covalent bond with the provisos that D3, D4, J3, J4 and K2 are each carbon and at least one of D1, D2, J1, J2 and K1 is selected from the group consisting of O, S, and N wherein, when D1, D2, J19 J2 and K1 are selected from the group consisting of C, O, S, covalent bond, and N, no more than one of D1, D2, J1, J2 and K1 can be a covalent bond, no more than one of D1, D2, J1 J2 and K1 can be O, no more than one of D1, D2, J1, J2 and K1 can be S, one of D1, D2, J1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 can be N;
n is an integer selected from 1 through 4;
X is oxy;
R16 is selected from the group consisting of hydrido, acyl, aroyl, and trialkylsilyl;
R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
R2 is selected from the group consisting of hydrido, hydroxy, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;
R3 is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
Y is selected from the group consisting of covalent single bond and (C(R14)2)q wherein q is an integer selected from 1 through 2;
R14 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
Z is selected from the group consisting of covalent single bond, (C(R15)2)q wherein q is an integer selected from 1 through 2, and (CH(R15))jxe2x80x94Wxe2x80x94(CH(R15))k wherein j and k are integers independently selected from 0 through 2;
W is oxy;
R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;
R5, R6, R7, R10, R11, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxaniido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl,alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;
R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R12, and R12 and R13 spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8 can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R12, and R12 and R13 can be used at the same time.
In a more specific embodiment of compounds of Formula VII-H,
D1, D2, J1, J2 and K1 are each carbon;
D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that at least one of D3, D4, J3, J4 and K2 is selected from the group consisting of O, S, and N, wherein no more than one of D3, D4, J3, J4 and K2 can be a covalent bond, no more than one of D3, D4, J3, J4 and K2 can be O, no more than one of D3, D4, J3, J4 and K2 can be S, one of D3, D4, J3, J4 and K2 must be a covalent bond when two of D3, D4, J3, J4 and K2 are O and S, and no more than four of D3, D4, J3, J4 and K2 can be N;
n is an integer selected from 1 through 3;
X is oxy;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;
R16 is selected from the group consisting of acetyl, benzoyl, dimethyl tert-butylsilyl, hydrido, and trimethylsilyl;
R2 is selected from the group consisting of hydrido, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, trifluoromethyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl;
R3 is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl.
In a more specific embodiment of compounds of Formula VII-H,
D3, D4, J3, J4 and K2 are each carbon;
D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that at least one of D1, D2, J1, J2 and K1 is selected from the group consisting of O, S, and N, wherein no more than one of D1, D2, J1, J2 and K1 can be a covalent bond, no more than one of D1, D2, J 1, J2 and K1 can be O, no more than one of D1, D2, J1, J2 and K1 can be S, one of D1, D2, J1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 can be N;
n is an integer selected from 1 through 3;
X is oxy;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;
R16 is selected from the group consisting of acetyl, benzoyl, dimethyl tert-butylsilyl, hydrido, and trimethylsilyl;
R2 is selected from the group consisting of hydrido, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, trifluoromethyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl;
R3 is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl.
In a preferred embodiment of compounds of Formula VII-H, the compounds correspond to the Formula VII (also referred to herein as generic phenyl tertiary 2-heteroalkylamines): 
or a pharmacuetically acceptable salt thereof, wherein;
n is an integer selected from 0 through 4;
X is selected from the group consisting of O, H, F, S, S(O), NH, N(OH), N(alkyl), and N(alkoxy);
R16 is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of any aromatic substituent selected from the group consisting of R4, R8, R9, and R13 to form a heterocyclyl ring having from 5 through 10 contiguous members with the proviso that said linear spacer moiety is other than covalent single bond when R2 is alkyl;
R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
R2 is selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, aryl, aralkyl, alkyl, alkenyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocyanoalkyl, and dicyanoalkyl, carboalkoxycyanoalkyl;
R3 is selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, aroyl, heteroaroyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl;
Y is selected from the group consisting of covalent single bond and (C(R14)2)q wherein q is an integer selected from 1 through 2;
R14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;
Z is selected from the group consisting of covalent single bond, (C(R15)2)q wherein q is an integer selected from 1 through 2, and (CH(R15))jxe2x80x94Wxe2x80x94(CH(R15))k wherein j and k are integers independently selected from 0 through 2;
W is selected from the group consisting of O, C(O), C(S), C(O)N(R14), C(S)N(R14), (R14)NC(O), (R14)NC(S), S, S(O), S(O)2, S(O)2N(R14), (R14)NS(O)2, and N(R14) with the proviso that R14 is other than cyano;
R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;
R5, R6, R7, R10, R11, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxanido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylarido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl;
R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R12, and R12 and R13 can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R12, and R12 and R13 can be used at the same time.
In a preferred embodiment of compounds of Formula VII, compounds have the Formula VII-2: 
wherein;
n is an integer selected from 1 through 4;
R16 is selected from the group consisting of hydrido, acyl, aroyl, and trialkylsilyl;
R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
R2 is selected from the group consisting of hydrido, hydroxy, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;
R3 is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
Y is selected from the group consisting of covalent single bond and (C(R14)2)q wherein q is an integer selected from 1 through 2;
R14 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
Z is selected from the group consisting of covalent single bond, (C(R15)2)q wherein q is an integer selected from 1 through 2, and (CH(R15))jxe2x80x94Wxe2x80x94(CH(R15))k wherein j and k are integers independently selected from 0 through 2;
W is oxy;
R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;
R5, R6, R7, R10, R11, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroaiylalkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;
R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R12, and R12 and R13 spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryloxylene with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8 can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R12, and R12 and R13 can be used at the same time.
In a more preferred embodiment of compounds of Formula VII-2,
n is an integer selected from 1 through 2;
R1 is selected from the group consisting of haloalkyl and haloalkoxyalkyl;
R16 is hydrido;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y is selected from the group consisting of a covalent single bond and alkylene;
Z is selected from the group consisting of a covalent single bond and alkylene;
R14 is selected from the group consisting of hydrido, alkyl, and haloalkyl;
R15 is selected from the group consisting of hydrido, alkyl, and haloalkyl;
R4, R8, R9, and R13 are ndependendy selected from the group consisting of hydrido and halo;
R5, R6, R7, R10, R11, and R12 are independensy selected from the group consisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
In an even more preferred embodiment of compounds of Formula VII-2,
n is the integer 1;
R16 is hydrido;
R1 is haloalkyl;
R2 is selected from the group consisting of hydrido, alkyl, haloalkyl, aryl, and haloalkoxy;
R3 is selected from the group consisting of hydrido, alkyl, and haloalkyl;
Y is alkylene;
Z is covalent single bond;
R14 is hydrido;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido and halo;
R5, R6, R7, R10, R11 and R12 are independently selected from the group consisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, aralkanoylalkoxy, aralkenoyl, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, and heteroaryloxyalkyl.
In an embodiment of compounds of Formula VII-2,
n is an integer selected from 1 to 3;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;
R16 is selected from the group consisting of acetyl, benzoyl, dimethyl tert-butylsilyl, hydrido, and trimethylsilyl;
R2 is selected from the group consisting of hydrido, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, phenyl, trifluoromethyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl;
R3 is selected from the group consisting of hydrido, hydroxy, cyano, acetyl, methoxy, ethoxy, methyl, ethyl, propyl, vinyl, phenyl, methoxymethyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, chloromethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, pentafluorophenyl, and pentafluorophenoxymethyl.
In a preferred embodiment of compounds of Formula VII-2,
n is the integer 1;
R16 is hydrido;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, trifluoromethyl, 1,1,2,2-etrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, ethyl, vinyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
In a even more preferred embodiment of compounds of Formula VII-2,
n is the integer 1;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R16 is hydrido;
R2 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethyl, trifluoromethoxymethyl, 1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl;
In a most preferred embodiment of compounds of Formula VII-2,
n is the integer 1;
R1 is selected from the group consisting of trifluoromethyl and pentafluoroethyl;
R16 is hydrido;
R2 is selected from the group consisting of hydrido, phenyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl;
In another embodiment of compounds of Formula VII, compounds have the Formula Cyclo-VII: 
wherein:
R16 is taken together with R4, R8, R9 or R13 to form a spacer selected from the group consisting of a covalent single bond and a linear spacer moiety having a chain length of 1 to 4 atoms to form a heterocyclyl ring having from 5 through 10 contiguous members with the proviso that said linear spacer moiety is other than covalent single bond when R2 is alkyl;
n is an integer selected from 1 through 3;
X is selected from the group consisting of O, S, NH, N(alkyl), and N(alkoxy);
R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
R2 is selected from the group consisting of hydrido, hydroxy, hydroxyalkyl, aryl, aralkyl, alkyl, alkenyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocyanoalkyl, and dicyanoalkyl, carboalkoxycyanoalkyl;
R3 is selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, aroyl, heteroaroyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboxamide, and carboxamidoalkyl;
Y is selected from the group consisting of covalent single bond and (C(R14)2)q wherein q is an integer selected from 1 through 2;
R14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;
Z is selected from the group consisting of covalent single bond, (C(R15)2)q wherein q is an integer selected from 1 through 2, and (CH(R15))jxe2x80x94Wxe2x80x94(CH(R15))k wherein j and k are integers independently selected from 0 through 2;
W is selected from the group consisting of O, C(O), S, S(O), and S(O)2;
R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
R4, R8, R9, and R13 can be independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl; R5, R6, R7, R10, R11, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamnino, heteroarylamninoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, heteroaralkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylaamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl;
R5 and R6, R6 and R7, R7 and R8, R9 andR10, R10 and R11, R11 and R12, and R12 and R13 can be independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R5 and R6, R6 and R7, and R7 and R8, can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R12, and R12 and R13 can be used at the same time.
In an embodiment of compounds of Formula Cyclo-VII,
n is the integer 1;
X is selected from the group consisting of O, NH, and S;
R16 is taken together with R4, R8, R9 or R13 to form a spacer selected from the group consisting of a covalent single bond, CH2, CH(CH3), CF2, C(O), C(S), and SO2;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, vinyl, trifluoromethyl, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;
R3 is selected from the group consisting of hydrido, methyl, ethyl, vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl.
In another embodiment of compounds of Formula Cyclo-VII, compounds have the formula: 
n is the integer 1;
X is oxy;
R16 and R4 are taken together to form a covalent single bond;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, vinyl, trifluoromethyl, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, 2,2,3,3,3-pentafluoropropyl, and heptafluoropropyl;
R3 is selected from the group consisting of hydrido, methyl, ethyl, vinyl, phenyl, 4-trifluoromethylphenyl, methoxymethyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl.
In another embodiment of compounds of Formula VII, compounds have the Formula VII-3: 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl and haloalkenyloxyalkyl;
R2 is hydroxyalkyl;
Y is selected from the group consisting of covalent single bond and (C(R14)2)q wherein q is an integer selected from 1 through 2;
R14 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
Z is selected from the group consisting of covalent single bond, (C(R15)2)q wherein q is an integer selected from 1 through 2, and (CH(R15))jxe2x80x94Wxe2x80x94(CH(R15))k wherein j and k are integers independently selected from 0 through 2;
W is oxy;
R5 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido, halo, haloalkyl, and alkyl;
R5, R6, R7, R10, R11, and R12 are independently selected from the group consisting of perhaloaryloxy, alkanoylalkyl, alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio, heteroarylsulfonyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, alkylsulfonamido, monoarylamidosulfonyl, arylsulfonyl, heteroarylthio, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;
R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R12, and R12 and R13 spacer pairs can be independently selected from the group consisting of alkylene, alkenylene, alkylenedioxy, aralkylene, diacyl, haloalkylene, and aryldioxylene with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8 can be used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R12, and R12 and R13 can be used at the same time.
In an embodiment of compounds of Formula VII-3,
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, chloromethyl, trifluoromethoxymethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, and pentafluorophenoxymethyl;
R2 is hydroxymethyl, 1-hydroxyethyl, and 1,2-dihydroxyethyl.
In another embodiment of compounds of Formula VII, compounds have the Formula VII-4: 
wherein;
X is oxy;
R1 is selected from the group consisting of haloalkyl and haloalkoxyalkyl;
R16 is hydrido;
R2 and R3 are taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, and a heterocyclyl having from 4 through 8 contiguous members;
Y is selected from the group consisting of a covalent single bond and alkylene;
Z is selected from the group consisting of a covalent single bond and alkylene;
R14 is selected from the group consisting of hydrido, alkyl, and haloalkyl;
R15 is selected from the group consisting of hydrido, alkyl, and haloalkyl;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido and halo;
R5, R6, R7, R10, R11, and R12 are independently selected from the group consisting of perhaloaryloxy, N-aryl-N-alkylamino, heterocyclylalkoxy, heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-arylcarboxamnidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, heterocyclylcarbonyl, hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
In an embodiment of compounds of Formula VII-4,
X is oxy;
R16 is hydrido;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 and R3 spacer pair is selected from the group consisting of xe2x80x94CH2SCH2xe2x80x94, xe2x80x94CH2OCH2xe2x80x94, xe2x80x94CH2CH(R17)xe2x80x94, xe2x80x94CHxe2x95x90C(R17)xe2x80x94, xe2x80x94CH2S(O)2CH2xe2x80x94, xe2x80x94CH2CH2CH(R17)xe2x80x94, xe2x80x94CH2CH(R17)CH2xe2x80x94, xe2x80x94CH2CHxe2x95x90C(R17)xe2x80x94, xe2x80x94CH(R17)CHxe2x95x90CHxe2x80x94, xe2x80x94CH2C(R17)xe2x95x90CHxe2x80x94, xe2x80x94CH(R17)C(O)N(R17)xe2x80x94, xe2x80x94C(O)N(R17)CH(R17)xe2x80x94, xe2x80x94CH(R17)C(O)NHCH2xe2x80x94, xe2x80x94CH2C(O)NHCH(R17)xe2x80x94, xe2x80x94CH(R17)CH(R17)C(O)NHxe2x80x94, xe2x80x94C(O)NHCH(R17)CH(R17)xe2x80x94, xe2x80x94CH2CH(R17)CH2CH2xe2x80x94, xe2x80x94CH(R17)CH2CH2CH2xe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, xe2x80x94CHxe2x95x90CHCH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHCHxe2x95x90CHxe2x80x94, xe2x80x94CH2CH2CH2CH2CH2xe2x80x94, xe2x80x94CH2CH2CHxe2x95x90CHCH2xe2x80x94, xe2x80x94(CH2)2Oxe2x80x94, xe2x80x94(CH2CHR17)Oxe2x80x94, xe2x80x94(CF2)2Oxe2x80x94, xe2x80x94SCH2CH2xe2x80x94, xe2x80x94S(O)CH2CH2xe2x80x94, xe2x80x94CH2S(O)CH2xe2x80x94, xe2x80x94CH2S(O)CH2CH2xe2x80x94, xe2x80x94S(O)2CH2xe2x80x94, xe2x80x94CH2N(R17)Oxe2x80x94, xe2x80x94CH2CH2C(O)xe2x80x94, xe2x80x94CH2C(O)NR17xe2x80x94, and xe2x80x94CH2NR17CH2xe2x80x94 wherein R17 is selected from the group consisting of H, CH3, OCH3, CF3, CH2CH3, F, Cl, CH2OH, and OH.
In an embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII,
Y is selected from the group consisting of a covalent single bond, methylene, 2-fluoroethylidene, ethylidene, 2,2-difluoroethylidene, and 2,2,2-trifluoroethylidene;
Z is group selected from the group consisting of covalent single bond, oxy, methyleneoxy, methylene, ethylene, ethylidene, 2-fluoroethylidene, 2,2-difluoroethylidene, and 2,2,2-trifluoroethylidene;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido and fluoro;
R5 and R10 are independently selected from the group consisting of acetoxy, 3-acetamidophenoxy, 3-acetylphenoxy, 4-acetylphenylsulfonyl, amino, 4acetylphenylthio, acetylthio, 3-aminobenzyloxy, 4-aminobenzyloxy, 4-aminophenoxy, 3-aminophenyl, benzoyl, benzoylamido, benzoylmethoxy, benzyl, N-benzylamidocarbonyl, benzylamino, 3-benzylimidazol-4-ylmethoxy, N-benzyl-N-methylamidocarbonyl, benzyloxy, 4-benzyloxybenzyloxy, 4-benzyiphenoxy, 4-benzylpiperidinyl, bromo, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, bromomethyl, 4-bromo-2-nitrophenoxy, 2-bromobenzyloxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-bromothiophen-3-ylthio, butoxy, 4-butoxyphenoxy, N-butylylcarboxamnido, N-butyl-N-methylcarboxamido, N-butylethoxycarbonylphenylamino, 4-butylphenoxy, carboxy, carboxamidomethoxy, 3-carboxybenzyloxy, 4-carboxybenzyloxy, 4-carboxyphenyl, 5-carboxypyrid-3-yloxy, chloro, 3-chlorobenzyl, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chlorofluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chloro-2-hydroxypropoxy, 4-chloro-3-methylphenoxy, 4-chloro-3-methylbenzyl, 2-chloro-4-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chloro-2-fluorophenoxy, 3-chloro-4-fluorophenylsulfonylamido, 4-chlorophenyl, 3-chlorophenylamino, 4-chlorophenylamino, 5-chlorophenylthiophen-3-ylmethoxy, 5-chloropyrid-3-yloxy, 4-chlorothiophen-2-ylmethylthio, cyano, 3-cyanobenzyloxy, 4cyanobenzyloxy, 4-(2-cyano-2-ethoxycarbonylacetyl)phenylamino, N-(2-cyanoethyl)methylphenylamino, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, 4-cyanophenyl, 3-cyanophenylamino, 4-cyanophenylamino, 3-cyanopropoxy, cyclobutoxy, cyclobutyl, cyclohexylamidocarbonyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, N-cyclopentylamidocarbonyl, cyclopentylcarbonyl, 4-cyclopentylphenxoy, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 3,5-dichlorobenzyloxy, 3,5-dichloro-4-methylphenoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 3,5-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichloro-4-methoxyphenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-dichlorophenyl, 3,4-difluorophenoxy, 2,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorobenzyloxy, 2,6-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,4-difluorobenzyloxy, difluoromethoxy, 2,5-difluorophenoxy, 3,5-difluorophenylamino, 3,5-dimethoxyphenoxy, dimethylamino, N,N-dimethylcarbtoxamido, 2-(N,N-dimethylamino)ethoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,5-dimethyl-4-(N,N-dimethylamino)phenyl, 3,4-dimethoxyphenylamino, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 1,1-dimethylhydroxymethyl, 3,3-dimethyl-2-oxobutoxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, ethoxycarbonyl, 3-ethoxycarbonylphenylamino, 4-ethoxycarbonylphenylamino, 4-ethoxycarbonylbutoxy, 4-ethoxyphenoxy, ethyl, 4,4-ethylenedioxypiperidinyl, N-ethyl-N-methylcarboxamido, 3-ethylphenoxy, 4-ethylaminophenoxy, 4-ethylbenzyloxy, 3-ethyl-5-methylphenoxy, N-ethyl-3-methylphenylamino, N-ethylmethoxyphenylamino, fluoro, 4-fluorobenzylamino, 4-fluoro-3-methylbenzyl, 2-fluoro-3-methylbenzyloxy, 4-fluoro-3-methylphenyl, 4-fluorobenzoyl, 4-fluoro-3-methylbenzoyl, 3-fluorobenzyloxy, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 5-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamidocarbonylamido, 4-fluorophenylamino, 4-fluorobenzoylamido, 4-fluorobenzylamidocarbonyl, 2-fluorotrifluoromethylphenoxy, 4-fluoro-2-trifluoromethylphenoxy, 2-fluoro-4-chloromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, N-(2,2,3,3,4,4,4-heptafluorobutyl)amidocarbonyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, hydrazinocarbonyl, hydrido, hydroxy, 2-hydroxyethoxy, 1-hydroxyisobutyl, 3-hydroxy-2,2-dimethylpropoxy, hydroxymethyl, 3-hydroxymethylphenoxy, 4-hydroxyphenoxy, 3-hydroxypropoxy, 2-hydroxy-3,3,3-trifluoropropoxy, 4-imidazol-1-yl-phenoxy, indol-5-yloxy, iodo, 3-iodobenzyloxy, isobutylamino, isobutoxy, N-isobutoxycarbonylamido, isobutyl, isobutyryl, isobutyrylamido, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, isopropylamidocarbonyl, isopropylamidocarbonylamido, 4-isopropylbenzyloxy, N-isopropyl-N-methylamino, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, isopropylsulfonyl, isopropylsulfonylamido, isoquinolin-3-yloxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, methoxy, 3-methoxybenzoylamido, 3-methoxybenzyl, methoxycarbonyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylbenzyloxy, 4-methoxycarbonylbenzyloxy, 2-methoxyethoxy, 3-methoxycarbonylmethoxy, 3-methoxycarbonylprop-2-enyloxy, methoxymethyl, N-methoxy-N-methylcarboxamido, 3-methoxyphenoxy, 4-methoxyphenoxy, 4-methoxy-3-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methoxyphenylamidocarbonylamido, 4-methoxyphenylthio, methyl, N-methyl-4-methoxyphenylamino, 4-methylbenzyl, 3-methylbutyl, 3-methylphenoxy, 4-methylsulfonylphenyl, 3-methylmethylthiophenoxy, 3-methylbenzyloxy, 4-methylbenzyloxy, 2-methyl-3-nitrophenoxy, 2-methyl-5-nitrophenoxy, 4-methylphenoxy, 4-methylphenyl, N-methyl-N-phenylamidocarbonyl, N-methyl-N-propylcarboxamido, 4-(5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl)phenylamino, 3-methylphenylsulfonylamido, 4-methylpiperazin-1-ylcarbonyl, 1-methylpropoxy, 3-methylbut-2-enyloxy, 2-methylpyrid-6-yl, 3-methylpyrid-2-yl, 2-methylpyrid-3-yloxy, 2-methylpyrid-5-yloxy, N-methylpyrrol-2-yl, 4-methylsulfonylphenylsulfonyl, 4-methylsulfonylphenylthio, 4-methylthiophenoxy, 4-methylthiophenyl, 4-methylthiobenzyl, morpholin-4-ylcarbonyl, 2-naphthyloxy, N-neopentylamidocarbonyl, nitro, 3-nitrobenzyl, 3-nitrobenzyloxy, 4-nitrobenzyloxy, 2-nitrophenoxy, 3-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylsulfonyl, 3-nitrophenylsulfonylamido, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-oxobutoxy, 5-oxohexoxy, N-oxypyrid-3-ylmethylsulfonyl, 2,3,4,5,6-pentafluorobenzyloxy, pentafluoroethyl, pentafluoroethylthio, 4-(2,3,4,5,6-pentafluorophenyl)-2,3,5,6-tetrafluorophenoxy, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, 3-phenoxybenzyloxy, phenyl, phenylamidocarbonylamiido, 1-(N-phenylcarboxamnido)ethoxy, phenylamino, 4-phenylbenzyloxy, 1-phenylethoxy, phenylhydroxymethyl, 3-phenylphenoxy, 4-phenylphenoxy, phenylsulfonyl, phenylsulfonylamido, 2-phenylsulfonylethoxy, phenylthio, 1-piperidinyl, piperidinylcarbonyl, piperidin-4-ylsulfonyl, piperidinylthio, hexahydropyran-4-yloxy, 4-propanoyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propylphenylamino, 4-propoxyphenoxy, pyrid-2-yl, pyrid-3-yl, pyrid-3-ylcarboxamido, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyridylmethoxy, pyrid-2-yloxy, pyrid-3-yloxy, pyrid-2-ylmethylthio, pyridylthio, pyrimid-2-yl, pyrimnid-2-yloxy, pyrimid-5-yloxy, pyrrolin-1-ylcarbonyl, 2-(pyrrolidin-1-yl)ethoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy,tert-butoxy, N-ten-butylamidocarbonyl, 4-tert-butylbenzyl, 4-tert-butylbenzyloxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 4-tert-butylphenyl, tetrazol-5-yl, 3-(1,1,2,2-tetrafluoroethoxy)benzylamino, 1,1,2,2-tetrafluoroethoxy, 2,3,5,6-tetrafluoromethoxybenzyloxy, 2,3,5,6-tetrafluoro trifluoromethylbenzyloxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazolyl, thiazol-5-yl, thiol, 4-thiophenoxy, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,4,6-trifluorobenzyloxy, N-(4,4,4-trifluorobutyl)methoxyphenylamino, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, N-(2,2,2-trifluoroethyl)amidocarbonyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxybenzylamidocarbonyl, 3-trifluoromethoxybenzylamidocarbonylhydrazinocarbonyl, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenylamino, trifluoromethyl, 3-trifluoromethylbenzylamine, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 3,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3,5-bis-trifluoromethylphenyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenylamnidocarbonylamido, 4-trifluoromethylphenylamino, 3-trifluoromethylphenylsulfonylamido, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3,4,5-trimethoxyphenylamino, 3-trifluoromethylpyrid-2-yl, 3-trifluoromethylpyrid-2-yloxy, 5-trifluoromethylpyrid-2-yloxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;
R6 and R11 are independently selected from the group consisting of acetoxy, benzyloxy, bromo, butoxy, butoxycarbonyl, chloro, 4-chlorophenyl, 3,4-dichlorophenoxy, cyano, 2-cyanophenyl, difluoromethoxy, ethoxy, fluoro, hydrido, hydroxy, methoxy, methoxycarbonyl, methyl, methylsulfonyl, morpholin-4-yl, nitro, octyl, phenoxy, phenyl, phenylethenyl, phenylethynyl, propoxy, thiophen-2-yl, trifluoromethyl, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethoxy;
R7 and R12 are independently selected from the group consisting of benzyloxy, hydrido, fluoro, hydroxy, methoxy, and trifluoromethyl;
R5 and R6 can be taken together to form a spacer group selected from the group consisting of benzylidene, 5-bromobenzylidene, ethylene-1,2-dioxy, tetrafluoroethylene-1,2-dioxy, 1,4-butadienyl, methylene-1,1-dioxy, phenoxylidene, and propylene-1,3-dioxy;
R6 and R7 can be taken together to form a spacer group selected from the group consisting of benzylidene, 5-bromobenzylidene, ethylene-1,2-dioxy, tetrafluoroethylene-1,2-dioxy, 1,4-butadienyl, methylene-1,1-dioxy, phenoxylidene, and propylene-1,3-dioxy;
R10 and R11 can be taken together to form a spacer group selected from the group consisting of benzylidene, ethylene-1,2-dioxy, methylene-1,1-dioxy, phthaloyl, and tetrafluoroethylene-1,2-dioxy;
R11 and R12 can be taken together to form a spacer group selected from the group consisting of benzylidene, ethylene-1,2-dioxy, methylene-1,1-dioxy, phthaloyl, and tetrafluoroethylene-1,2-dioxy;
R12 and R13 can be the spacer group 1,4-butadienyl.
In a preferred embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII,
Y is selected from the group consisting of methylene, ethylene, and ethylidene;
Z is covalent single bond;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido and fluoro;
R5 and R10 are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chlorofluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chlorofluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,5-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,5-dimethybenzyl, 3,4-dimethylbenz yloxy, 3,5-dimethylbenzyloxy, 2,2-dimethyipropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 3-dthyilbenzynoxy, 3-ethy ophenoxy, 3-dethy laminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 3,4-fluoro-3-methylphenoxy, 3-fluoro-4-methyeylphenoxy, 3-defluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-2-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluor-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 3-fluorophenylarohno, 2-fluoro-4-fluoromethyphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methylmethylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-peniafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazolfyl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;
R6 and R11 are independendy selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;
R7 and R12 are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
In an even more preferred embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII,
Y is methylene;
Z is covalent single bond;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido and fluoro;
R5 and R10 are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chlorofluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloromethylphenoxy, 3-chlorofluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,5-difluorophenyl, 2,3-difluorophenoxy, 2,5-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylamninophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;
R6 and R11 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;
R7 and R12 are independently selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
In a most preferred embodiment of compounds of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII,
Y is methylene;
Z is covalent single bond;
R4, R8, R9, and R13 are independently selected from the group consisting of hydrido and fluoro;
R5 is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 3-isopropylphenoxy, 3-methylphenoxy, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 3-trifuoromethylbenzyloxy, and 3-trifluoromethylthiophenoxy;
R10 is selected from the group consisting of cyclopentyl, 1,1,2,2-tetrafluoroethoxy, 2-furyl, 1,1-bis-trifluoromethyl-1-hydroxymethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl, and trifluoromethylthio;
R6 and R11 are independently selected from the group consisting of fluoro and hydrido;
R7 and R12 are independently selected from the group consisting of hydrido and fluoro.
The use of generic terms in the description of the compounds are herein defined for clarity.
Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol xe2x80x9cCxe2x80x9d represents a carbon atom. The symbol xe2x80x9cOxe2x80x9d represents an oxygen atom. The symbol xe2x80x9cNxe2x80x9d represents a nitrogen atom. The symbol xe2x80x9cPxe2x80x9d represents a phosphorus atom. The symbol xe2x80x9cSxe2x80x9d represents a sulfur atom. The symbol xe2x80x9cHxe2x80x9d represents a hydrogen atom. Double letter elemental symbols are used as defined for the elements of the periodical table (i.e., Cl represents chlorine, Se represents selenium, etc.).
As utilized herein, the term xe2x80x9calkylxe2x80x9d, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d and xe2x80x9calkylthioxe2x80x9d, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like. The term xe2x80x9calkynylxe2x80x9d refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term xe2x80x9chydridoxe2x80x9d denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a xe2x80x9chydroxylxe2x80x9d radical, one hydrido radical may be attached to a carbon atom to form a xe2x80x9cmethinexe2x80x9d radical (xe2x95x90CHxe2x80x94), or two hydrido radicals may be attached to a carbon atom to form a xe2x80x9cmethylenexe2x80x9d (xe2x80x94CH2xe2x80x94) radical.
The term xe2x80x9ccarbonxe2x80x9d radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
The term xe2x80x9ccyanoxe2x80x9d radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
The term xe2x80x9chydroxyalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.
The term xe2x80x9calkanoylxe2x80x9d embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.
The term xe2x80x9calkylenexe2x80x9d radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, ethylidene, methylethylene, and isopropylidene.
The term xe2x80x9calkenylenexe2x80x9d radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH2xe2x95x90C), 1,2-vinylidene (xe2x80x94CHxe2x95x90CHxe2x80x94), and 1,4-butadienyl (xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94).
The term xe2x80x9chaloxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term xe2x80x9chaloalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are xe2x80x9clower haloalkylxe2x80x9d radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The term xe2x80x9chydroxyhaloalkylxe2x80x9d embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above. Examples of xe2x80x9chydroxyhaloalkylxe2x80x9d radicals include hexafluorohydoxypropyl.
The term xe2x80x9chaloalkylene radicalxe2x80x9d denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are xe2x80x9clower haloalkylenexe2x80x9d radicals having one to about six carbon atoms. Examples of xe2x80x9chaloalkylenexe2x80x9d radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
The term xe2x80x9chaloalkenylxe2x80x9d denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
The terms xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkoxyalkylxe2x80x9d embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term xe2x80x9calkoxyalkylxe2x80x9d also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tet-butoxy alkyls. The xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d and xe2x80x9chaloalkoxyalkylxe2x80x9d radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.
The terms xe2x80x9calkenyloxyxe2x80x9d and xe2x80x9calkenyloxyalkylxe2x80x9d embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term xe2x80x9calkenyloxyalkylxe2x80x9d also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are xe2x80x9clower alkenyloxyxe2x80x9d radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The xe2x80x9calkenyloxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkenyloxyxe2x80x9d radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy.
The term xe2x80x9chaloalkoxyalkylxe2x80x9d also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term xe2x80x9chaloalkenyloxyxe2x80x9d also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term xe2x80x9chaloalkenyloxyalkylxe2x80x9d also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.
The term xe2x80x9calkylenedioxyxe2x80x9d radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of xe2x80x9calkylenedioxyxe2x80x9d radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term xe2x80x9chaloalkylenedioxyxe2x80x9d radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of xe2x80x9chaloalkylenedioxyxe2x80x9d radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The term xe2x80x9cfusedxe2x80x9d means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term xe2x80x9cfusedxe2x80x9d is equivalent to the term xe2x80x9ccondensedxe2x80x9d. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
The term xe2x80x9cperhaloarylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
The term xe2x80x9cheterocyclylxe2x80x9d embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4-nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed xe2x80x9cheteroarylxe2x80x9d radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said xe2x80x9cheterocyclylxe2x80x9d group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heterocyclic radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imnidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-hiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and the like.
The term xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals xe2x80x94SO2xe2x80x94. xe2x80x9cAlkylsulfonylxe2x80x9d, embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. xe2x80x9cAlkylsulfonylalkylxe2x80x9d, embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. xe2x80x9cHaloalkylsulfonylxe2x80x9d, embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. xe2x80x9cHaloalkylsulfonylalkylxe2x80x9d, embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term xe2x80x9caminosulfonylxe2x80x9d denotes an amino radical attached to a sulfonyl radical.
The term xe2x80x9csulfinylxe2x80x9d, whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals xe2x80x94S(O)xe2x80x94. xe2x80x9cAlkylsulfinylxe2x80x9d, embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. xe2x80x9cAlkylsulfinylalkylxe2x80x9d, embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. xe2x80x9cHaloalkylsulfinylxe2x80x9d, embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. xe2x80x9cHaloalkylsulfinylalkylxe2x80x9d, embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are xe2x80x9clower aralkylxe2x80x9d radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.
The term xe2x80x9cheteroaralkylxe2x80x9d embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term xe2x80x9cperhaloaralkylxe2x80x9d embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
The term xe2x80x9caralkylsulfinylxe2x80x9d, embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. xe2x80x9cAralkylsulfinylalkylxe2x80x9d, embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9caralkylsulfonylxe2x80x9d, embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. xe2x80x9cAralkylsulfonylalkylxe2x80x9d, embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9ccycloalkylxe2x80x9d embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are xe2x80x9clower cycloalkylxe2x80x9d radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term xe2x80x9ccycloalkylalkylxe2x80x9d embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are xe2x80x9clower cycloalkylalkylxe2x80x9d radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term xe2x80x9ccycloalkenylxe2x80x9d embraces radicals having three to ten carbon atoms and one or more carboncarbon double bonds. Preferred cycloalkenyl radicals are xe2x80x9clower cycloalkenylxe2x80x9d radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term xe2x80x9chalocycloalkylxe2x80x9d embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are xe2x80x9clower halocycloalkylxe2x80x9d radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term xe2x80x9chalocycloalkenylxe2x80x9d embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.
The term xe2x80x9ccycloalkoxyxe2x80x9d embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy. The term xe2x80x9ccycloalkoxyalkylxe2x80x9d also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl. The xe2x80x9ccycloalkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chalocycloalkoxyxe2x80x9d and xe2x80x9chalocycloalkoxyalkylxe2x80x9d radicals.
The term xe2x80x9ccycloalkylalkoxyxe2x80x9d embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.
The term xe2x80x9ccycloalkenyloxyxe2x80x9d embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term xe2x80x9ccycloalkenyloxyalkylxe2x80x9d also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The xe2x80x9ccycloalkenyloxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chalocycloalkenyloxyxe2x80x9d and xe2x80x9chalocycloalkenyloxyalkylxe2x80x9d radicals.
The term xe2x80x9ccycloalkylenedioxyxe2x80x9d radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group. Examples of xe2x80x9calkylenedioxyxe2x80x9d radicals include 1,2-dioxycyclohexylene.
The term xe2x80x9ccycloalkylsulfinylxe2x80x9d, embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above. xe2x80x9cCycloalkylsulfinylalkylxe2x80x9d, embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term xe2x80x9cCycloalkylsulfonylxe2x80x9d, embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. xe2x80x9cCycloalkylsulfonylalkylxe2x80x9d, embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9ccycloalkylalkanoylxe2x80x9d embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane.
The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are xe2x80x9clower alkylthioxe2x80x9d radicals having one to six carbon atoms. An example of xe2x80x9clower alkylthioxe2x80x9d is methylthio (CH3xe2x80x94Sxe2x80x94). The xe2x80x9calkylthioxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkylthioxe2x80x9d radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.
The term xe2x80x9calkyl aryl aminoxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl methoxyaniline, and N-methyl-4-trifluoromethoxyaniline.
The terms alkylarino denotes xe2x80x9cmonoalkylarinoxe2x80x9d and xe2x80x9cdialkylaminoxe2x80x9d containing one or two alkyl radicals, respectively, attached to an amino radical.
The terms arylamino denotes xe2x80x9cmonoarylaminoxe2x80x9d and xe2x80x9cdiarylaminoxe2x80x9d containing one or two aryl radicals, respectively, attached to an amino radical. Examples of such radicals include N-phenylamino and N-naphthylamino.
The term xe2x80x9caralkylaminoxe2x80x9d, embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes xe2x80x9cmonoaralkylamioxe2x80x9d and xe2x80x9cdiaralkylaminoxe2x80x9d containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes xe2x80x9cmonoaralkyl monoalkylaminoxe2x80x9d containing one aralkyl radical and one alkyl radical attached to an amino radical. The term xe2x80x9carylsulfinylxe2x80x9d embraces radicals containing an aryl radical, as defined above, attached to a divalent S(xe2x95x90O) atom. The term xe2x80x9carylsulfinylalkylxe2x80x9d denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
The term xe2x80x9carylsulfonylxe2x80x9d, embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above. xe2x80x9carylsulfonylalkylxe2x80x9d, embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term xe2x80x9cheteroarylsulfinylxe2x80x9d embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent S(xe2x95x90O) atom. The term xe2x80x9cheteroarylsulfinylalkylxe2x80x9d denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term xe2x80x9cHeteroarylsulfonylxe2x80x9d, embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. xe2x80x9cHeteroarylsulfonylalkylxe2x80x9d, embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9caryloxyxe2x80x9d embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 4-tet-butylphenoxy, 3-pentafluoroethylphenoxy, and 3-(1,1,2,2-tetrafluoroethoxy)phenoxy.
The term xe2x80x9caroylxe2x80x9d embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
The term xe2x80x9caralkanoylxe2x80x9d embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.
The term xe2x80x9caralkoxyxe2x80x9d embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are xe2x80x9clower aralkoxyxe2x80x9d radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and 2-phenylethoxy.
The term xe2x80x9caryloxyalkylxe2x80x9d embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.
The term xe2x80x9chaloaryloxyalkylxe2x80x9d embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.
The term xe2x80x9cheteroaroylxe2x80x9d embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
The term xe2x80x9cheteroaralkanoylxe2x80x9d embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.
The term xe2x80x9cheteroaralkoxyxe2x80x9d embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are xe2x80x9clower heteroaralkoxyxe2x80x9d radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
The term xe2x80x9chaloheteroaryloxyalkylxe2x80x9d embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
The term xe2x80x9cheteroarylaminoxe2x80x9d embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.
The term xe2x80x9cheteroarylaminoalkylxe2x80x9d embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino.
The term xe2x80x9cheteroaryloxyxe2x80x9d embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4-pyridyloxy.
The term xe2x80x9cheteroaryloxyalkylxe2x80x9d embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.
The term xe2x80x9carylthioxe2x80x9d embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
The term xe2x80x9carylthioalkylxe2x80x9d embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.
The term xe2x80x9calkylthioalkylxe2x80x9d embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term xe2x80x9calkoxyalkylxe2x80x9d embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
The term xe2x80x9ccarbonylxe2x80x9d denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term xe2x80x9ccarboxyxe2x80x9d embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term xe2x80x9ccarboxamidexe2x80x9d embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term xe2x80x9ccarboxamidoalkylxe2x80x9d embraces carboxamide radicals, as defined above, attached to an alkyl group. The term xe2x80x9ccarboxyalkylxe2x80x9d embraces a carboxy radical, as defined above, attached to an alkyl group. The term xe2x80x9ccarboalkoxyxe2x80x9d embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term xe2x80x9ccarboaralkoxyxe2x80x9d embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term xe2x80x9cmonocarboalkoxyalkylxe2x80x9d embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term xe2x80x9cdicarboalkoxyalkylxe2x80x9d embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term xe2x80x9cmonocyanoalkylxe2x80x9d embraces one cyano radical, as defined above, attached to an alkyl group. The term xe2x80x9cdicyanoalkylenexe2x80x9d embraces two cyano radicals, as defined above, attached to an alkyl group. The term xe2x80x9ccarboalkoxycyanoalkylxe2x80x9d embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group.
The term xe2x80x9cacylxe2x80x9d, alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylaamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of xe2x80x9cacylxe2x80x9d are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. The term xe2x80x9chaloalkanoylxe2x80x9d embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl. The term xe2x80x9cdiacylxe2x80x9d, alone or in combination, means having two or more carbonyl or thionocarbonyl groups bonded to a radical selected from, for example, alkylene, alkenylene, alkynylene, haloalkylene, alkoxyalkylene, aryl, heterocyclyl, heteroaryl, aralkyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl. Examples of xe2x80x9cdiacylxe2x80x9d are phthaloyl, malonyl, succinyl, adipoyl, and the like.
The term xe2x80x9cbenzylidenylxe2x80x9d radical denotes substituted and unsubstituted benzyl groups having attachment points for two covalent bonds. One attachment point is through the methylene of the benzyl group with the other attachment point through an ortho carbon of the phenyl ring. The methylene group is designated for attached to the lowest numbered position. Examples include the base compound benzylidene of structure: 
The term xe2x80x9cphenoxylidenylxe2x80x9d radical denotes substituted and unsubstituted phenoxy groups having attachment points for two covalent bonds. One attachment point is through the oxy of the phenoxy group with the other attachment point through an ortho carbon of the phenyl ring. The oxy group is designated for attached to the lowest numbered position. Examples include the base compound phenoxylidene of structure: 
The term xe2x80x9cphosphonoxe2x80x9d embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term xe2x80x9cdialkoxyphosphonoxe2x80x9d denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term xe2x80x9cdiaralkoxyphosphonoxe2x80x9d denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term xe2x80x9cdialkoxyphosphonoalkylxe2x80x9d denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term xe2x80x9cdiaralkoxyphosphonoalkylxe2x80x9d denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
Said xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d, xe2x80x9calkanoylxe2x80x9d, xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cbenzylidenylxe2x80x9d, xe2x80x9cphenoxylidenylxe2x80x9d, xe2x80x9chydroxyalkylxe2x80x9d, xe2x80x9chaloalkylxe2x80x9d, xe2x80x9chaloalkylenexe2x80x9d, xe2x80x9chaloalkenylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9calkenyloxylxe2x80x9d, xe2x80x9calkenyloxyalkylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d, xe2x80x9carylxe2x80x9d, xe2x80x9cperhaloarylxe2x80x9d, xe2x80x9chaloalkoxyxe2x80x9d, xe2x80x9chaloalkoxyalkylxe2x80x9d, xe2x80x9chaloalkenyloxyxe2x80x9d, xe2x80x9chaloalkenyloxyalkylxe2x80x9d, xe2x80x9calkylenedioxyxe2x80x9d, xe2x80x9chaloalkylenedioxyxe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, xe2x80x9cheteroarylxe2x80x9d, xe2x80x9chydroxyhaloalkylxe2x80x9d, xe2x80x9calkylsulfonylxe2x80x9d, xe2x80x9chaloalkylsulfonylxe2x80x9d, alkylsulfonylalkylxe2x80x9d, xe2x80x9chaloalkylsulfonylalkylxe2x80x9d, xe2x80x9calkylsulfinylxe2x80x9d, xe2x80x9calkylsulfinylalkylxe2x80x9d, xe2x80x9chaloalkylsulfinylalkylxe2x80x9d, xe2x80x9caralkylxe2x80x9d, xe2x80x9cheteroaralkylxe2x80x9d, xe2x80x9cperhaloaralkylxe2x80x9d, xe2x80x9caralkylsulfonylxe2x80x9d, xe2x80x9caralkylsulfonylalkylxe2x80x9d, xe2x80x9caralkylsulfinylxe2x80x9d, xe2x80x9caralkylsulfinylalkylxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9ccycloalkylalkanoylxe2x80x9d, xe2x80x9ccycloalkylalkylxe2x80x9d, xe2x80x9ccycloalkenylxe2x80x9d, xe2x80x9chalocycloalkylxe2x80x9d, xe2x80x9chalocycloalkenylxe2x80x9d, xe2x80x9ccycloalkylsulfinylxe2x80x9d, xe2x80x9ccycloalkylsulfinylalkylxe2x80x9d, xe2x80x9ccycloalkylsulfonylxe2x80x9d, xe2x80x9ccycloalkylsulfonylalkylxe2x80x9d, xe2x80x9ccycloalkoxyxe2x80x9d, xe2x80x9ccycloalkoxyalkylxe2x80x9d, xe2x80x9ccycloalkylalkoxyxe2x80x9d, xe2x80x9ccycloalkenyloxyxe2x80x9d, xe2x80x9ccycloalkenyloxyalkylxe2x80x9d, xe2x80x9ccycloalkylenedioxyxe2x80x9d, xe2x80x9chalocycloalkoxyxe2x80x9d, xe2x80x9chalocycloalkoxyalkylxe2x80x9d, xe2x80x9chalocycloalkenyloxyxe2x80x9d, xe2x80x9chalocycloalkenyloxyalkylxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9chaloalkylthioxe2x80x9d, xe2x80x9calkylsulfinylxe2x80x9d, xe2x80x9caminoxe2x80x9d, xe2x80x9coxyxe2x80x9d, xe2x80x9cthioxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d, xe2x80x9carylaminoxe2x80x9d, xe2x80x9caralkylaminoxe2x80x9d, xe2x80x9carylsulfinylxe2x80x9d, xe2x80x9carylsulfinylalkylxe2x80x9d, xe2x80x9carylsulfonylxe2x80x9d, xe2x80x9carylsulfonylalkylxe2x80x9d, xe2x80x9cheteroarylsulfinylxe2x80x9d, xe2x80x9cheteroarylsulfinylalkylxe2x80x9d, xe2x80x9cheteroarylsulfonylxe2x80x9d, xe2x80x9cheteroarylsulfonylalkylxe2x80x9d, xe2x80x9cheteroarylaminoxe2x80x9d, xe2x80x9cheteroarylaminoalkylxe2x80x9d, xe2x80x9cheteroaryloxyxe2x80x9d, xe2x80x9cheteroaryloxylalkylxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9caroylxe2x80x9d, xe2x80x9caralkanoylxe2x80x9d, xe2x80x9caralkoxyxe2x80x9d, xe2x80x9caryloxyalkylxe2x80x9d, xe2x80x9chaloaryloxyalkylxe2x80x9d, xe2x80x9cheteroaroylxe2x80x9d, xe2x80x9cheteroaralkanoylxe2x80x9d, xe2x80x9cheteroaralkoxyxe2x80x9d, xe2x80x9cheteroaralkoxyalkylxe2x80x9d, xe2x80x9carylthioxe2x80x9d, xe2x80x9carylthioalkylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d, xe2x80x9cacylxe2x80x9d and xe2x80x9cdiacylxe2x80x9d groups defined above may optionally have 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamnino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
The term xe2x80x9cspacerxe2x80x9d can include a covalent bond and a linear moiety having a backbone of 1 to 7 continous atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from xe2x95x90C(H)xe2x80x94, xe2x95x90C(R17)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(R17)xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94CH(OH)xe2x80x94, xe2x95x90C(OH)xe2x80x94, xe2x80x94CH(OR17)xe2x80x94, xe2x95x90C(OR17)xe2x80x94, and xe2x80x94C(O)xe2x80x94 wherein R17 is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6 atoms with a side chain. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, ethenyl, xe2x80x94CHxe2x95x90CH(OH)xe2x80x94, xe2x80x94OCH2Oxe2x80x94, xe2x80x94O(CH2)2Oxe2x80x94, xe2x80x94NHCH2xe2x80x94, xe2x80x94OCH(R17)Oxe2x80x94, xe2x80x94O(CH2CHR17)Oxe2x80x94, xe2x80x94OCF2Oxe2x80x94, xe2x80x94O(CF2)2Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(H)xe2x80x94, xe2x80x94N(H)Oxe2x80x94, xe2x80x94N(R17)Oxe2x80x94, xe2x80x94N(R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NR17xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, S(O)CH2xe2x80x94, xe2x80x94CH2C(O)xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x95x90C(OH)xe2x80x94, xe2x80x94CH(OR17)xe2x80x94, xe2x95x90C(OR17)xe2x80x94, S(O)2CH2xe2x80x94, and xe2x80x94NR17CH2xe2x80x94 and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylanrino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis-and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention.
The terms xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond (xe2x80x9ccisxe2x80x9d) or on opposite sides of the double bond (xe2x80x9ctransxe2x80x9d).
Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or xe2x80x9cExe2x80x9d and xe2x80x9cZxe2x80x9d geometric forms.
Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the xe2x80x9cketoxe2x80x9d form and in part or principally as one or more xe2x80x9cenolxe2x80x9d forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both xe2x80x9cketoxe2x80x9d and xe2x80x9cenolxe2x80x9d tautomeric forms.
Some of the compounds described herein may contain one or more amide carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the xe2x80x9cketoxe2x80x9d form and in part or principally as one or more xe2x80x9cenolxe2x80x9d forms of each amide group present. Compounds of the present invention having amnidic carbonyl groups are meant to include both xe2x80x9cketoxe2x80x9d and xe2x80x9cenolxe2x80x9d tautomeric forms. Said amide carbonyl groups may be both oxo (Cxe2x95x90O) and thiono (Cxe2x95x90S) in type.
Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the xe2x80x9ciminexe2x80x9d form and in part or principally as one or more xe2x80x9cenaminexe2x80x9d forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both xe2x80x9ciminexe2x80x9d and xe2x80x9cenaminexe2x80x9d tautomeric forms.
The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes are as follows: xe2x80x9cAAxe2x80x9d represents amino acids, xe2x80x9cBINAPxe2x80x9d represents 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, xe2x80x9cBocxe2x80x9d represents tert-butyloxycarbonyl, xe2x80x9cBOPxe2x80x9d represents benzotriazol-1-yl-oxy-tris-(dimethylamino), xe2x80x9cbuxe2x80x9d represents butyl, xe2x80x9cdbaxe2x80x9d represents dibenzylideneacetone, xe2x80x9cDCCxe2x80x9d represents 1,3-dicyclohexylcarbodiimide, xe2x80x9cDIBAIxe2x80x9d represents diisobutylaluminum hydride, xe2x80x9cDIPEAxe2x80x9d represents diisopropylethylarine, xe2x80x9cDMFxe2x80x9d represents dimethylformamide, xe2x80x9cDMSOxe2x80x9d represents dimethylsulfoxide, xe2x80x9cFmocxe2x80x9d represents 9-fluorenylmethoxycarbonyl, xe2x80x9cLDAxe2x80x9d represents lithium diisopropylaminde, xe2x80x9cPHTHxe2x80x9d represents a phthaloyl group, xe2x80x9cpnZxe2x80x9d represents 4-nitrobenzyloxycarbonyl, xe2x80x9cPTCxe2x80x9d represents a phase transfer catalyst, xe2x80x9cp-TsOHxe2x80x9d represents paratoluenesulfonic acid, xe2x80x9cTBAFxe2x80x9d represents tetrabutylammonium fluoride, xe2x80x9cTBTUxe2x80x9d represents 2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, xe2x80x9cTEAxe2x80x9d represents triethylamine, xe2x80x9cTFAxe2x80x9d represents trifluoroacetic acid, xe2x80x9cTHFxe2x80x9d represents tetrahydrofuran, xe2x80x9cTMSxe2x80x9d represents trimethylsilyl, and xe2x80x9cZxe2x80x9d represents benzyloxycarbonyl.
The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of a compound of Formula V-H: 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R19, X, Y, and Z are as defined above for the compounds of Formula V-H;
or a pharmaceutically-acceptable salt thereof.
As a further embodiment, compounds of the present invention of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, or a pharmaceutically-acceptable salt thereof as defined above and further including those, wherein R16 is a covalent single bond linked to a point of bonding of R4 or R8 when R2 is alkyl, R2 and R14 are taken together to form a xe2x80x94Nxe2x95x90 spacer group, and R2 and R15 are taken together to form a xe2x80x94Nxe2x95x90 spacer group, comprise a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, of the present invention or a pharmaceutically-acceptable salt thereof.
Compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII including those, wherein R16 is a covalent single bond linked to a point of bonding of R4 or R8 when R2 is alkyl, R2 and R14 are taken together to form a xe2x80x94Nxe2x95x90 spacer group, and R2 and R15 are taken together to form a xe2x80x94Nxe2x95x90 spacer group, are capable of inhibiting activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as peripheral vascular disease, hyperlipidaemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both, or a procedure to study the mechanism of action of the cholesteryl ester transfer protein (CETP) to enable the design of better inhibitors. The compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
Also included in the family of compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII are the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula V-H may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula V-H include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,Nxe2x80x2-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and CycloVII by reacting, for example, the appropriate acid or base with the compounds of Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII.
Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formula V-H in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.
The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient In the case of microcapsules, the encapsulating agent may also function as the membrane.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
All mentioned references are incorporated by reference as if here written.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.
The compounds of the present invention can be synthesized, for example, according to the following procedures of Schemes 1 through 59 below, wherein the substituents are as defined for Formulas V-H, V, VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII above except where further noted.
Synthetic Schemes 1 and 2 shows the preparation of compounds of formula XIII (xe2x80x9cGeneric Secondary Aminesxe2x80x9d) which are intermediates in the preparation of the compounds of the present invention corresponding to Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-2-hydroxyalkylaminesxe2x80x9d), and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminesxe2x80x9d) wherein A and Q are independently aryl and heteroaryl. Schemes 1 and 2, taken together, prepare tertiary oxyalkylamine compounds of the present invention by addition of a halogenated, oxygen containing precursor to a secondary amine to introduce an oxy containing alkyl group wherein the two groups making up the secondary amine both are made up of aromatic groups or both groups contain aromatic rings wherein said aromatic rings maybe 0 to 2 aryl rings and 0 to 2 heteroaryl rings.
The xe2x80x9cGeneric Iminexe2x80x9d corresponding to Formula XII can be prepared through dehydration techniques generally known in the art and the preferred technique depending on the nature of xe2x80x9cGeneric Amine-1xe2x80x9d of Formula X by reacting it with the xe2x80x9cGeneric Carbonyl Compoundxe2x80x9d of Formula XI. For example, when Z is a covalent bond, methylene, methine substituted with another subsitutent, ethylene, or another subsituent as defined in Formula V-H, the two reactants (X and XI) react by refluxing them in an aprotic solvent, such as hexane, toluene, cyclohexane, benzene, and the like, using a Dean-Stark type trap to remove water. After about 2-8 hours or until the removal of water is complete, the aprotic solvent is removed in vacuo to yield the xe2x80x9cGeneric Iminexe2x80x9d of Formula XII. Alternately, when Z is an oxygen, the xe2x80x9cGeneric Iminexe2x80x9d is an oxime derivative. Oxime type xe2x80x9cGeneric Iminexe2x80x9d compounds are readily prepared from the corresponding O-substituted hydroxylamine and the appropriate aldehyde or ketone type xe2x80x9cGeneric Carbonyl Compoundxe2x80x9d. Suitable procedures are described by Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley and Sons and by Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley and Sons, which are incorporated herein by reference. Alternately, when Z is a nitrogen, the xe2x80x9cGeneric Iminexe2x80x9d is a hydrazone derivative. Hydrazone type xe2x80x9cGeneric Iminexe2x80x9d compounds are readily prepared from the corresponding hydrazine and the appropriate aldehyde or ketone type xe2x80x9cGeneric Carbonyl Compoundxe2x80x9d. Suitable procedures for forming the hydrazone imines are also described by Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley and Sons, and by Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley and Sons, which are incorporated herein by reference.
Scheme 1 shows the preparation of xe2x80x9cGeneric Iminexe2x80x9d compounds in which the amine functionality is bonded to Z; Z is bonded to A; and Y is bonded to Q. One of skill in the art will recognize that A and Q as defined can be structurally interchanged to prepare xe2x80x9cGeneric Iminexe2x80x9d compounds with similar, identical or different structures.
The xe2x80x9cGeneric Secondary Aminesxe2x80x9d of Formula XIII can be prepared from the corresponding xe2x80x9cGeneric Iminexe2x80x9d of Formula XII in several ways.
For example, in one synthetic scheme (Reduction Methdo-1), which is preferred when Z is a nitrogen, the xe2x80x9cGeneric Iminexe2x80x9d hydrazone of Formula XII is partially or completely dissolved in lower alkanols such as ethanol or like solvent containing sufficient organic acid such as acetic acid or mineral acid such as HCl or sulfuric acid to neutralize the hydrazone as described in WO Patent Application No. 9738973, Swiss Patent CH 441366 and U.S. Pat. Nos. 3,359,316 and 3,334,017, which are incorporated herein by reference. The resulting mixture is then hydrogenated at 0-100xc2x0 C., more preferrably 20-50xc2x0 C., and most preferrably between 20-30xc2x0 C. and pressures of 10-200 psi hydrogen or more preferrably between 50-70 psi hydrogen in the presence of a noble metal catalyst such as PtO2. The mixture is cooled, and a base such as sodium carbonate or sodium hydroxide added until the solution is neutral to just alkaline (pH 6-8).
Isolation of the desired product can be accomplished, for example, by removing the ethanol, adding water, and extracting the aqueous-organic mixture twice with a solvent, such as diethyl ether or methylene chloride, that is immiscible with water. The combined solvent extract is washed with saturated brine, dried with a drying agent such as anhydrous magnesium sulfate, and concentrated in vacuo to yield the xe2x80x9cGeneric Secondary Aminesxe2x80x9d hydrazine of Formula XIII. If needed the xe2x80x9cGeneric Secondary Aminesxe2x80x9d hydrazine can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.
In another synthetic scheme (Reduction Method-2), which is preferred when Z is a single bond or carbon, the xe2x80x9cGeneric Iminexe2x80x9d of Formula XII is slurried in a lower alcohol such as ethanol, methanol or like solvent at 0-10xc2x0 C. and solid sodium borohydride is added in batches over 5-10 minutes at 0-10xc2x0 C. with stirring. The reaction mixture is stirred below 10xc2x0 C. for 30-90 minutes and then is warmed gradually to 15-30xc2x0 C. After about 1-10 hours, the mixture is cooled and acid is added until the aqueous layer was just acidic (pH 5-7).
Isolation of the desired product can be accomplished, for example, by extracting the aqueous layer twice with a solvent, such as diethyl ether or methylene chloride, that is immiscible with water. The combined solvent extract is washed with saturated brine, dried with a drying agent such as anhydrous MgSO4, and concentrated in vacuo to yield the xe2x80x9cGeneric Secondary Aminesxe2x80x9d amine, aniline, or amine of Formula XIII. If needed the xe2x80x9cGeneric Secondary Aminesxe2x80x9d amine, aniline, or amine derivative can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.
In yet another synthetic scheme (Reduction Method-3), which is preferred when Z is an oxygen, the xe2x80x9cGeneric Iminexe2x80x9d oxime of Formula XII is slurried in a lower alcohol solvent such methanol or like solvent at 0-10xc2x0 C. and acidified to a pH less than 4. Solid sodium cyanoborohydride is added in batches over 30-90 minutes at 0-20xc2x0 C. with stirring and addition of a suitable organic or mineral acid to keep the pH at or below 4. The reaction mixture is stirred and warmed gradually to about 20-25xc2x0 C. After about 1-10 hours, the mixture is cooled and base added until the mixture was just slightly alkaline.
Isolation of the desired product can be accomplished, for example, by removing the methanol or other low boiling solvent in vacuo. The residue is slurried with water and aqueous-organic mixture is extracted twice with a solvent, such as diethyl ether or methylene chloride, that is immiscible with water. The combined solvent extract is washed with saturated brine, dried with a drying agent such as anhydrous MgSO4, and concentrated in vacuo to yield the xe2x80x9cGeneric Secondary Aminesxe2x80x9d hydroxylamine of Formula XIII. If needed the xe2x80x9cGeneric Secondary Aminesxe2x80x9d hydroxylamine can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.
The xe2x80x9cGeneric Secondary Aminesxe2x80x9d of Formula XIII can also be prepared, according to Scheme 1 by two alkylation procedures based on the nucleophilic substitution of bromides by amines. In one procedure, xe2x80x9cGeneric Amine-1xe2x80x9d of Formula X is reacted with xe2x80x9cGeneric Bromide-1xe2x80x9d of Formula XXI. In another alkylation procedure, xe2x80x9cGeneric Amine-2xe2x80x9d of Formula XXII is reacted together with xe2x80x9cGeneric Bromide-2xe2x80x9d of Formula XXIII.
In one synthetic alkylation scheme (Alkylation Methdo-1), a xe2x80x9cGeneric Amine-1xe2x80x9d of Formula X is reacted with a xe2x80x9cGeneric Bromide-2xe2x80x9d of Formula XXIII as described in Vogel""s Textbook of Practical Organic Chemistry, Fifth Edition, 1989, pages 902 to 905 and references cited therein all of which are incorporated herein by reference. In this procedure, the xe2x80x9cGeneric Amine-1xe2x80x9d is placed in a reaction vessel equipped with a reflux condenser with the capability to either cool or heat the vessel as dictated by the reaction. A suitable xe2x80x9cGeneric Amine-1xe2x80x9d will be selected from primary amine and primary aromatic amine classes of compounds. Cooling may be needed and used should the reaction prove strongly exothermic. Heating may be needed and used to drive the reaction to completion. A suitable solvent may also be used to dissolve the xe2x80x9cGeneric Amine-1xe2x80x9d. Suitable solvents are hydrocarbons such as toluene, hexane, xylene, and cyclohexane, ethers, amides such as dimethylformamide, esters such as ethyl acetate, ketones such as acetone, and nitriles such as acetonitrile or mixtures of two or more of these solvents. A suitable base is also added to the reaction vessel. Suitable bases include cesium carbonate, calcium carbonate, sodium carbonate and sodium bicarbonate. The base will normally be added in at least a stoichmetric quantity compared to the xe2x80x9cGeneric Amine-1xe2x80x9d so as to neutralize liberated acid as it forms.
The xe2x80x9cGeneric Bromide-1xe2x80x9d of Formula XXI is then added to the reaction vessel in portions so as to minimize the rate of heat evolution and minimize the concentration of the xe2x80x9cGeneric Bromide-1xe2x80x9d. The xe2x80x9cGeneric Bromide-1xe2x80x9d will be selected from primary and secondary organic alkyl and substituted alkyl halide compounds. The halide will preferrably be a bromide although iodides and chlorides may also be generally used. One of skill in the art will also be able to readily select and utilize organic alkyl and substituted alkyl compounds containing readily displaceable primary and secondary groups such as tosylates, mesylates, triflates, and the like. Alternately, the halides can be generally prepared from the corresponding alcohols by reaction with, for example, concentrated hydrohalic acids such as HBr or by reaction with phosphorus trihalides such as PBr3 as described in Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley and Sons, which are incorporated herein by reference. The appropriate alcohols can be converted to tosylates, mesylates, and triflates using procedures described below.
Addition of the xe2x80x9cGeneric Bromide-1xe2x80x9d is carried out over a period of a few minutes to several hours at temperatures between 0 and 150xc2x0 C.
Preferrably, the addition will take 30-120 minutes at a temperature of 0 to 50xc2x0 C. The reaction can be stirred until completion. Completion can be monitored, for example, spectroscopically using nuclear magnetic resonance or chromatographically using thin layer, liquid, or gas chromatographic procedures. If the reaction does not proceed to completion, the reactants may be heated until completion is obtained and verified.
Isolation of the desired product can be accomplished, for example, when a water immiscible solvent was used for the reaction, by adding water to the finished reaction. Additional base such as sodium carbonate can be added to ensure the reaction is basic (pH of 9 to 11). The organic layer containing the xe2x80x9cGeneric Secondary Aminexe2x80x9d is washed with saturated brine, dried with a drying agent such as anhydrous MgSO4, and concentrated in vacuo to yield the xe2x80x9cGeneric Secondary Aminexe2x80x9d amine, aniline, or amine of Formula XIII. If needed the xe2x80x9cGeneric Secondary Aminexe2x80x9d amine, aniline, or amine derivative can be further purified by crystallization, distillation at reduced pressure, or liquid chromatography.
In a second synthetic alkylation scheme (Alkylation Method-2), a xe2x80x9cGeneric Amine-2xe2x80x9d of Formula XXII is reacted with a xe2x80x9cGeneric Bromide-2xe2x80x9d of Formula XXIII in a method employing pallladium catalyzed carbon-nitrogen bond formation. Suitable procedures for this conversion are described in Wagaw and Buchwald, J. Org. Chem.(1996), 61, 7240-7241, Wolfe, Wagaw and Buchwald, J. Am. Chem. Soc. (1996), 118, 7215-7216, and Wolfe and Buchwald, Tetrahedron Letters (1997), 38(36), 6359-6362 and references cited therein all of which are incorporated herein by reference. The preferred xe2x80x9cGeneric Bromide-2xe2x80x9d of Formula XXIII are generally aryl bromides, aryl triflates, and heteroaryl bromides.
The xe2x80x9cGeneric Amine-1xe2x80x9d and xe2x80x9cGeneric Amine-2xe2x80x9d arines, hydroxylamines, and hydrazines, the xe2x80x9cGeneric Carbonyl Compoundxe2x80x9d aldehydes, ketones, hydrazones, and oximes, and xe2x80x9cGeneric Bromide-1xe2x80x9d and xe2x80x9cGeneric Bromide-2xe2x80x9d halides, tosylates, mesylates, triflates, and precursor alcohols required to prepare the xe2x80x9cGeneric Secondary Aminexe2x80x9d compounds are available from commercial sources, can be prepared by one skilled in the art from published procedures, and/or can be obtained using specific procedures shown in Schemes 42, 43, and 44. Commercial sources include but are not limited to Aldrich Chemical, TCI-America, Lancaster-Synthesis, Oakwood Products, Acros Organics, and Maybridge Chemical. Disclosed procedures for xe2x80x9cGeneric Aminexe2x80x9d amines, hydroxylamines, and hydrazines include Sheradsky and Nov, J. Chem. Soc., Perkin Trans.1 (1980), (12), 2781-6; Marcoux, Doye, and Buchwald, J. Am. Chem. Soc. (1997), 119, 1053-9; Sternbach and Jamison, Tetrahedron Lett. (1981), 22(35), 3331-4; U.S. Pat. No. 5,306,718; EP No. 314435; WO No. 9001874; WO No. 9002113; JP No. 05320117; WO No. 9738973; Swiss Patent No. CH 441366; U.S. Pat. Nos. 3,359,316 and 3,334,017; and references cited therein which are incorporated herein by reference. Representative specific xe2x80x9cGeneric Secondary Aminexe2x80x9d of Formula XIII compounds useful for the preparation of compounds of the present invention are listed in Tables 3, 4, and 5.
As summarized in the general Scheme 1 and specific descriptions above, Schemes 3, 4, 9, and 10 illustrate the principles of Scheme 1 for the preparation of specifically substituted xe2x80x9cSecondary Heteroaryl Aminesxe2x80x9d (XIIIA-H) having 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups and xe2x80x9cSecondary Phenyl Aminesxe2x80x9d (XIII-A) having two aryl groups.
Synthetic Scheme 2 shows the preparation of the class of compounds of the present invention corresponding to Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-2-hydroxyalkylaminesxe2x80x9d), and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminesxe2x80x9d) wherein A and Q are independently aryl and heteroaryl.
Derivatives of xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d and xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d, wherein A and Q are independently aryl and heteroaryl, in which the hetero atom (xe2x80x94Oxe2x80x94) is attached to an alkyl group removed from the amine by three or more carbons are readily prepared by anion chemistry using Method B of Scheme 2. The anion of xe2x80x9cGeneric Secondary Aminexe2x80x9d amines, hydroxylamines, and hydrazines of Formula XIII are readily formed by dissolving the specific amine, hydroxylamine, or hydrazine in an aprotic solvent, such as tetrahydrofuran, toluene, ether, dimethylformamide, and dimethylformamide, under anhydrous conditions. The solution is cooled to a temperature between xe2x88x9278 and 0xc2x0 C., preferrably between xe2x88x9278 and xe2x88x9260xc2x0 C. and the anion formed by the addition of at least one equivalent of a strong, aprotic, non-nucleophillic base such as NaH or n-butyllithium under an inert atmosphere for each acidic group present. Maintaining the temperature between xe2x88x9278 and 0xc2x0 C., preferrably between xe2x88x9278 and xe2x88x9260xc2x0 C., with suitable cooling, an appropriate alkyl halide, alkyl benzenesulfonate such as a alkyl tosylate, alkyl mesylate, alkyl triflate or similar alkylating reagent of the general structure, 
where M is a readily displaceable group such as chloride, bromide, iodide, tosylate, triflate, and mesylate. After allowing the reaction mixture to warm to room temperature, the reaction product is added to water, neutralized if necessary, and extracted with a water-immiscible solvent such as diethyl ether or methylene chloride. The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO4 and concentrated in vacuo to yield crude Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d) and Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d), wherein A and Q are independently aryl and heteroaryl. This material is purified, for example, by eluting through silica gel with 5-40% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d) and Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d). Products are tested for purity by HPLC. If necessary, Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d) and Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d) compounds are purified by additional chromatography or recrystallization. Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Examples of specific Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d) and Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d) compounds prepared are summarized in Tables 6 and 7.
Compounds of Formula (XXX), which can be used to prepare the xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d compounds of Tables 6 and 7, are given in Table 2. Reagents 1a and 2a in Table 2 are prepared from the corresponding alcohols. The tosylates are readily obtained by reacting the corresponding alcohol with tosyl chloride using procedures found in House""s Modem Synthetic Reactions, Chapter 7, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley and Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley and Sons, which are incorporated herein by reference.
A preferred procedure for Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl teliy 2-heteroalkylaminexe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-heteroalkylaminesxe2x80x9d) compounds, wherein the 2-hetero group is a hydroxyl, is Method A of Scheme 2. Oxirane reagents useful in Method A are exemplified, but not limited to those in Table 1. Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary 2-hydroxyalkylaminexe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminesxe2x80x9d) compounds are prepared by using xe2x80x9cGeneric Secondary Aminexe2x80x9d amines, hydroxylamines, and hydrazines of Formula XIII prepared above with oxiranes of the type listed in Table 1 and represented by the general structure: 
In some cases, the oxiranes are prepared by reaction of epoxidation reagents such as MCPBA and similar type reagents readily selectable by a person of skill-in-the-art with alkenes. Fieser and Fieser in Reagents for Organic Synthesis, John Wiley and Sons provides, along with cited references, numerous suitable epoxidation reagents and reaction conditions, which are incorporated herein by reference.
Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary 2-heteroalkylaminexe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-heteroalkylaminesxe2x80x9d) compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be prepared by using appropriate aziridines and thirranes according to Method A of Scheme 2. Aziridine and thiirane reagents useful in Method A are exemplified, but not limited to those in Table 1. These Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tert 2-heteroalkylaminexe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-heteroalkylaminesxe2x80x9d) compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be prepared by using xe2x80x9cGeneric Secondary Aminexe2x80x9d amines, hydroxylamines, and hydrazines of Formula XIII prepared above with aziridines and thiiranes of the type listed in Table 1 and represented by the general structure: 
wherein X is selected from N and S and R16 is hydrogen or another suitable group when X is N.
A mixture of a xe2x80x9cGeneric Secondary Aminexe2x80x9d amine, hydroxylamine, or hydrazine of Formula XIII and an oxirane of Formula XX are stirred and heated to 40-90xc2x0 C. for 5 to 48 hours in a tightly capped or contained reaction vessel. A Lewis acid such as ytterbium triflate in acetonitrile may be added to speed up reaction and improve yield. When a Lewis acid is used, the reaction should be carried out under inert, anhydrous conditions using a blanket of dry nitrogen or argon gas. After cooling to room temperature and testing the reaction mixture for complete reaction by thin layer chromatography or high pressure liquid chromatography (hplc), the reaction product is added to water and extracted with a water immiscible solvent such as diethyl ether or methylene chloride. (Note: If the above analysis indicates that reaction is incomplete, heating should be resumed until complete with the optional addition of more of the oxirane). The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO4 and concentrated in vacuo to yield crude Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl teriary 2-hydroxyalkylaminexe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminexe2x80x9d) compounds. This material is purified by eluting through silica gel with 5-40% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield the Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary 2-hydroxyalkylaminexe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminexe2x80x9d). Products are tested for purity by HPLC. If necessary, the Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary 2-hydroxyalkylaminexe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminexe2x80x9d) compounds are purified by additional chromatography or recrystallization. Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Examples of specific Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertary 2-hydroxyalkylaminexe2x80x9d) compounds prepared are summarized in Example Tables 1 through 54.
Specific Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary 2-heteroalkylaminexe2x80x9d) analogs of the xe2x80x9cPolycyclic Aryl tertiary -2-hydro xyalkylaminexe2x80x9d compounds summarized in Example Tables 1 through 54, wherein the hydroxyl or oxy group are replaced with an amino, substituted amino, aza, or thiol, can be prepared by using the appropriate aziridine reagents or thiirane reagents readily by adapting the procedures in the numerous specific Examples and Schemes disclosed in the present invention. Similarly, intermediates, in which the hydroxyl or oxy group of said intermediates are replaced with an amino, substituted amino, aza, or thiol, can be converted using the numerous specific Examples and Schemes disclosed in the present invention to other Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl teriry 2-heteroalkylaminexe2x80x9d) analogs of the xe2x80x9cPolycyclic Aryl tertiary -2-hydroxyalkylaminexe2x80x9d compounds.
As summarized in the general Scheme 2 and specific descriptions above, Schemes 5, 6, 7, and 11 illustrate the principles of Scheme 2 for the preparation of specifically substituted xe2x80x9cGeneric Substituted Polycyclic Aryl Tertiary OmegaHydroxyalkylaminesxe2x80x9d (V) having 2 aryl groups, xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl Tertiary OmegaHydroxyalkylaminesxe2x80x9d (V-H) having two aromatic substituents made up of 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups, xe2x80x9cGeneric Substituted Polycyclic Heteroaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d (VII-H) having two aromatic substituents made up of 0 to 2 aryl groups and 0 to 2 aromatic heterocyclyl groups, and xe2x80x9cGeneric Substituted Polycyclic Aryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d (VII) having two aryl groups.
Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-2-hydroxyalkylaminesxe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminesxe2x80x9d) can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1 to 7 and 9 to 11. Schemes 45 to 50 detail such procedures to prepare tertiary oxyalkylamine compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XVL (xe2x80x9cGeneric Substituted Alkylaminexe2x80x9d). Said halogenated, oxygen containing primary alkylamine XVL, formed in Schemes 45 and 48, is itself converted to secondary amines, VLX-H (xe2x80x9cHeteroaryl Alkyl Aminexe2x80x9d) and VLX (xe2x80x9cPhenyl Alkyl Aminexe2x80x9d), using procedures disclosed above. Primary alkylamine XVL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH (xe2x80x9cHeteroaryl Carbonylxe2x80x9d) and XI-A (xe2x80x9cPhenyl Carbonylxe2x80x9d) with azeotropic distillation to form imines, VL-H (xe2x80x9cHeteroaryl Iminexe2x80x9d) and VL (xe2x80x9cPhenyl Iminexe2x80x9d). Said imines VL-H and VL are then reduced with or without prior isolation by Reduction Methods 1, 2 or 3 as disclosed above and in Schemes 1, 3, and 9 to yield secondary amines, VLX-H (xe2x80x9cHeteroaryl Alkyl Amine) and VLX (xe2x80x9cPhenyl Alkyl Aminexe2x80x9d). Said secondary amine VLX-H can be converted according to Schemes 46 and 47 to VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylaminesxe2x80x9d). Using Schemes 49 and 50, VLX can be converted to VII (xe2x80x9cGeneric Substituted Polycyclic Phenyl Tertiary 2-hydroxyalkylaminesxe2x80x9d). Compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting VLX-H with an aryl bromide or aralkyl bromide instead of using an heteroaryl bromide or heteroaralkyl bromide as described in Schemes 46 and 47. Similarly, compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting VLX with an heteroaryl bromide or heteroaralkyl bromide instead of using an aryl bromide or aralkyl bromide as described in Schemes 49 and 50.
Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-2-hydroxyalkylaminesxe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylarinesxe2x80x9d) can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1 to 7, 9 to 11, and 45 to 50. Schemes 56,58, and 59 detail alternate procedures to prepare tertiary oxyalkylamine compounds of the present invention by initial formation of an halogenated, oxygen containing secondary alkylamines VLX and VLXX (xe2x80x9cPhenyl Alkylaminesxe2x80x9d) and VLXX-O (xe2x80x9cPhenyl Oxy Alkylaminesxe2x80x9d). Said secondary alkylamines VLX and VLXX (xe2x80x9cPhenyl Alkylaminesxe2x80x9d) and VLXX-O (xe2x80x9cPhenyl Oxy Alkylaminesxe2x80x9d) can be converted according to Schemes 56, 58 and 59 to VII (xe2x80x9cGeneric Substituted Polycyclic Aryl Tertiary 2-hydroxyalkylaminesxe2x80x9d) and VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylaminesxe2x80x9d) by reaction with appropriate aromatic halides such as aryl bromides and heteroaryl bromides as desired.
Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-2-hydroxyalkylaminesxe2x80x9d) and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminesxe2x80x9d) can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1 to 7, 9 to 11, 45 to 50, 56,58, and 59. Scheme 57 details another alternate procedure to prepare tertiary oxyalkylamine compounds of the present invention by reacting secondary amines XIII-A (xe2x80x9cSecondary Phenyl Aminexe2x80x9d) and XIIIA-H (xe2x80x9cSecondary Heteroaryl Aminexe2x80x9d) with a diazo ester. The intermediate glycinate tertiary amine can then be reduced, partially reoxidized to an aldehyde, and converted using a perfluoroalkyl trimethylsilyl compound (for example, trifluoromethyl-TMS) to the desired product, VII (xe2x80x9cGeneric Substituted Polycyclic Aryl Tertiary 2-hydroxyalkylaminesxe2x80x9d) and VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylaminesxe2x80x9d).
Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-3-hydroxyalkylaminesxe2x80x9d) and Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-3-hydroxyalkylaminesxe2x80x9d), in which the halogenated oxy containing alkyl side chain has three carbons between the amine and oxy group, can be prepared in a manner similar to procedures disclosed above and in Schemes 45 to 50. Schemes 30 to 35 detail such procedures to prepare tertiary 3-oxyalkylamine compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XL (xe2x80x9cGeneric Substituted Alkylaminexe2x80x9d). Said halogenated, oxygen containing primary alkylamine XL, formed in Schemes 30 and 33, is itself converted to secondary amines, LX-H (xe2x80x9cHeteroaryl Alkyl Amine) and LX (xe2x80x9cPhenyl Alkyl Aminexe2x80x9d), using procedures disclosed above. Primary alkylamine XL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH (xe2x80x9cHeteroaryl Carbonylxe2x80x9d) and XI-A (xe2x80x9cPhenyl Carbonylxe2x80x9d) with azeotropic distillation to form imines, L-H (xe2x80x9cHeteroaryl Iminexe2x80x9d) and L (xe2x80x9cPhenyl Iminexe2x80x9d). Said imines L-H and L are then reduced with or without prior isolation by Reduction Methods 1, 2 or 3 as disclosed above and in Schemes 1, 3, and 9 to yield secondary amines, LX-H (xe2x80x9cHeteroaryl Alkyl Amine) and LX (xe2x80x9cPhenyl Alkyl Aminexe2x80x9d). Said secondary amine LX-H can be converted according to Schemes 31 and 32 to V-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl Tertiary 3-hydroxyalkylaminesxe2x80x9d).
Using Schemes 34 and 35, LX can be converted to V (xe2x80x9cGeneric Substituted Polycyclic Phenyl Tertiary 3-hydroxyalkylaminesxe2x80x9d). Compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting LX-H with an aryl bromide instead of using an heteroaryl bromide as described in Schemes 31 and 32. Similarly, compounds of this invention in which one aromatic substituent is aryl and the other aromatic substitutent is heteroaryl can be readily prepared by reacting LX with an heteroaryl bromide instead of using an aryl bromide as described in Schemes 34 and 35.
A particularly useful procedure to prepare Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-3-hydroxyalkylaminesxe2x80x9d) and VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl Tertiary 2-hydroxyalkylaminesxe2x80x9d) compounds of the present invention in which the heteroaryl group is directly bonded is disclosed in Schemes 51 to 54. An halogenated, oxygen containing primary alkylamine XVL (xe2x80x9cGeneric Substituted Alkylaminexe2x80x9d) formed in Schemes 45 and 48 is itself converted by reaction with LXXI-AH (xe2x80x9cHeteroaryl Halidexe2x80x9d) to afford secondary amine VLXX-H (xe2x80x9cHeteroaryl Secondary Amine) using procedures disclosed in Scheme 51 and above. VLXX-H is converted to VII-H (xe2x80x9cGeneric Substituted Polycyclic Phenyl Heteroaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by alkylation chemistry with an aralkyl bromide or aralkyloxyalkyl bromide using either of two procedures disclosed in Scheme 52. Isolation and purification is effected as disclosed previously. An halogenated, oxygen containing primary alkylamine XL (xe2x80x9cGeneric Substituted Alkylaminexe2x80x9d) formed in Schemes 30 and 33 is itself also converted by reaction with LXXI-AH (xe2x80x9cHeteroaryl Halidexe2x80x9d) to afford secondary amine LXX-H (xe2x80x9cHeteroaryl Secondary Amine) using procedures disclosed in Scheme 53 and above. LXX-H is converted to V-H (xe2x80x9cGeneric Substituted Polycyclic Phenyl Heteroaryl Tertiary 3-hydroxyalkylaminexe2x80x9d) by alkylation chemistry disclosed in Scheme 54 and previously and as given above with reference to Scheme 52. Isolation and purification of V-H and VII-H are effected as disclosed previously.
Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-2-hydroxyalkylaminesxe2x80x9d), and Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminesxe2x80x9d) can themselves serve as intermediates for conversion to additional compounds of this invention. Compounds of Formula VII and the present invention useful as intermediates include those in which the R7 position substituent in Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl Tertiary 2-hydroxyalkylaminexe2x80x9d) is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other preferred compounds of Formula VII and the present invention useful as intermediates include those in which the R10 position substituent in Formula VII is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other compounds of Formula VII and the present invention useful as intermediates include those in which one or more of R6, R7, R11, and R12 substituents in Formula VII is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups.
Scheme 8 discloses the conversion of a 3-bromo substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with a phenol to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d). Scheme 12 discloses the conversion of a 3-bromo substituent at the R7 position in Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic 3-Bromoheteroaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with a phenol to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d).
Scheme 22 discloses the conversion of a 3-bromo substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aryl borinate to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Phenylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 23 discloses the conversion of a 3-bromo substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with a primary or secondary amine to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-R22aminoaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 40 discloses the conversion of a 3-bromo substituent at the R10 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aryl borinate to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Phenylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 41 discloses the conversion of a 3-bromo substituent at the R10 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Bromoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with a heteroaryl dibutyl tin compound to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Heteroarylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 21 discloses the conversion of a 3-bromomethyl substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Bromomethylaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aryl borinate to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Arylmethylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 13 discloses the conversion of a 3-hydroxyl substituent at the R17 position in Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aryl bromide or heteroaryl bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d).
Scheme 14 discloses the conversion of a 3-hydroxyl substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aryl bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 15 discloses the conversion of a 3-hydroxyl substituent at the R7 position in Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylarinexe2x80x9d) by reaction with an aralkyl bromide or heteroaralkyl bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic 3-Aralkyloxyaryl, 3-Heteroaralkyloxyaryl, 3-Heteroaralkyloxyheteroaryl, and 3-Aralkyloxyheteroaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d).
Scheme 16 discloses the conversion of a 3-hydroxyl substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aralkyl bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Aralkyloxyaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 20 discloses the conversion of a 3-hydroxyl substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an R17-bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-RI 7-oxyaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 19 discloses the conversion of a 3-thio substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-thioaryl Tertiary 2-hydroxyalkylamninexe2x80x9d) by reaction with an R17-bromide to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-R17thiaaryl Tertiary 2-Hydroxyalkylarinexe2x80x9d). xe2x80x9cGeneric Substituted Polycyclic 3-R17thiaaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d can be oxidized to sulfonyl compounds of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-R7sulfonylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 24 discloses the conversion of a 3-nitro substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Nitroaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by hydrogenation to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d). xe2x80x9cGeneric Substituted Polycyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d can be acylated to acyl amide compounds of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Acylarinoaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Schemes 25 and 26 disclose the conversion of a 3-amino substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Aminoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with carbonyl compounds to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-(Saturated Nitrogen Heterocycl-lyl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d and xe2x80x9cGeneric Substituted Polycyclic 3-(Unsaturated Nitrogen Heterocycl-lyl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d, respectively).
Scheme 27 discloses the conversion of a 3-methoxycarbonyl substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with amination reagents to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Carboxamidoaryl Tertiary 2-Hydroxyalkylamninexe2x80x9d).
Scheme 28 discloses the conversion of a 3-cyano substituent at the R7 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Cyanoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with organometallic reagents to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Acylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d). Said xe2x80x9cGeneric Substituted Polycyclic 3-Acylaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d, according to Scheme 29 can be reduced to hydroxyl compounds of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Hydroxysubstitutedmethylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 36 discloses the conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with amination reagents to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Carboxamidoaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 37 discloses the conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an organometallic reagent to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-(bis-R20-hydroxymethyl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 38 discloses the conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with lithium aluminum hydride to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Hydroxymethylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d). Scheme 39 discloses the conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an alkylation reagent to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-(bis-R2-hydroxymethyl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Scheme 55 discloses the conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction intially with an amidation reagent and then an R20-organometallic reagent to afford, after isolation and purification as described above for Schemes 2, 5, 6, 7, and 11, additional compounds of the present invention of Formula VII (xe2x80x9cGeneric Substituted Polycyclic 3-(R20-carbonyl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-2-hydroxyalkylaminesxe2x80x9d), Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminesxe2x80x9d) and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. The hydroxyl group X, wherein R16 is a hydrogen, of compounds of Formulas V, V-H, VII, and VII-H can be readily converted to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. Acylation to form a carboxylic acid ester is readily effected using a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. In like manner, compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one hydroxyl group present in the form of an alcohol or phenol can be acylated to its corresponding esters. Similarly, carbamic acid esters (urethans) can be obtained by reacting any hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one thiol group present can be converted to the corresponding thioesters derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide. Suitable procedures and methods for preparing these derivatives can be found in House""s Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley and Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley and Sons. Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII are available from commerical sources or the references cited above, which are incorporated herein by reference.
Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-2-hydroxyalkylaminesxe2x80x9d), Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminesxe2x80x9d) and other compounds of this invention posssessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety derivatives. The hydroxyl group X, wherein R16 is a hydrogen, of compounds of Formulas V, V-H, VII, and VII-H can be readily converted to ethers. Alkylation to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used. Such reactions are generally carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents, amine catalyst such as pyridine in an inert solvent. In like manner, compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one hydroxyl group present in the form of an alcohol or phenol can be alkylated to their corresponding ethers. Compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII that have at least one primary, secondary or tertiary amine group present can be converted to the corresponding quaternary ammonium derivatives. Quaternary ammonium derivatives can be prepared using the appropriate bromides, iodides, and sulfonates analogous to those used with alcohols and phenols. Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a tertiary amine, two with a secondary, and three with a primary). With primary and secondary amines, two and one equivalents, respectively, of an acid scavenger are used concurrently. Tertiary amines can be preparedfrom the corresponding primary or secondary amine by reductive alkylation with aldehydes and ketones using reduction methods 1, 2, or 3 as shown in Scheme 3. Suitable procedures and methods for preparing these derivatives can be found in House""s Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley and Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley and Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas V, V-H, VII, VII-H, and Cyclo-VII are available from commerical sources or the references cited above, which are incorporated herein by reference.
Formula V-H (xe2x80x9cGeneric Substituted Polycyclic Aryl and Heteroaryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula V (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary omegahydroxyalkylaminesxe2x80x9d), Formula VII (xe2x80x9cGeneric Substituted Polycyclic Aryl tertiary-2-hydroxyalkylaminesxe2x80x9d), Formula VII-H (xe2x80x9cGeneric Substituted Polycyclic Heteroaryl tertiary-2-hydroxyalkylaminesxe2x80x9d) and certain other compounds of this invention can be converted, according to Schemes 17 and 18, to the corresponding cyclic derivatives represented by the general designation xe2x80x9cTricyclic teriayy-oxyalkylaminesxe2x80x9d exmplified by Formula Cyclo-VII (xe2x80x9cSubstituted Tricyclic Phenyl teriary-2-oxyalkylaminesxe2x80x9d). The hydroxyl group X, wherein R16 is a hydrogen of compounds of Formulas V, V-H, VII, and VII-H can be cyclized to corresponding cyclic ethers. Compounds suitable for cyclization will normally have at least one leaving group within 5 to 10 continuous atoms of the hydroxyl group X wherein R16 is a hydrogen. Most preferrably the leaving group will be within 5 to 7 atoms of the hydroxyl group X so as to form a 5 to 7 membered ring heteroatom containing ring. When the leaving group is part of an aromatic ring system, the leaving group will be preferrably in an ortho position. Suitable leaving groups generally include halides, sulfates, sulfonates, trisubsituted amino, disubstituted sulfonium, diazonium, and like, and, in the case of aromatic systems, also includes nitro, alkoxy, aryloxy, heteroaryloxy, and alkylthio. When X-R16 is a thiol, amino, or substituted amino, the corresponding analogous sulfur and nitrogen analogs, Cyclo-VII (xe2x80x9cSubstituted Tricyclic Phenyl tenrzy-2-thioalkylamines and teriary-2-azaalkylaminesxe2x80x9d), of Formula Cyclo-VII (xe2x80x9cSubstituted Tricyclic Phenyl tertiary-2-oxyalkylaminesxe2x80x9d) can be obtained.
The cyclization reaction to form xe2x80x9cTricyclic tertiary-oxyalkylaminesxe2x80x9d can be accomplished by aromatic and aliphatic nucleophilic substitution reactions such as those disclosed in March""s Advanced Organic Chemistry, 4th Edition, John Wiley and Sons, especially at pages 293412 and 649-658 and the references cited therein, which are incorporated herein by reference. Hydroxyl containing suitably substituted compounds can be converted to a cyclic analog by heating a suitably substituted compound under anhydrous conditions in a suitable solvent, such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetraglyme, or hexamethylphosphoramide, in the presence of a suitable base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium tertary-butoxide, or lithium diisopropylamide. Alternately, sodium amide in anhydrous ammonia solvent can be used. Temperatures in the range of xe2x88x9220xc2x0 C. to 200xc2x0 C. can be used for time periods of 30 minutes to more than 24 hours. The preferred temperature can be selected by standard synthetic chemical technique balancing maximum yield, maximum purity, cost, ease of isolation and operation, and time required. Isolation of the xe2x80x9cTricyclic tertiary-oxyalkylaminesxe2x80x9d can be effected as described above for other tertiary-oxyalkylamines. Representative xe2x80x9cTricyclic teriary-oxyalkylaminesxe2x80x9d prepared using the methodology described above are included in Table 8.
The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
